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Aluminium–related osteomalacia: response to reverse osmosis water treatment
Kidney International, Vol. 32 (1987), pp. 96—101
Aluminium—related osteomalacia: Response to reverse osmosis water treatment GEORGE D. SMITH, ROBIN J. WINNEY, ALEXANDER MCLEAN, and JAMES S. ROBSON Department of Pathology, University Medical School, and Medical Renal Unit, Royal Infirmary, Edinburgh, Scotland, United Kingdom
In this paper we described seven chronic-hemodialysis patients with aluminium related osteomalacia who were subsethereby inhibiting mineralization of osteoid. Because this form of quently provided with reverse osmosis facilities, but had no osteomalacia is vitamin D resistant, the condition has often been other alteration in management. After three years, four patients
Aluminium—related osteomalacia: response to reverse osmosis water treatment. It is generally accepted that aluminium induces osteomalacia in chronic hemodialysis patients by binding to the calcification front,
showed a marked improvement in bone mineralization, whereas
assumed to be irreversible, although promising results have been
in the other three patients the skeletal pathology was un-
achieved recently by using a chelating agent for removal of aluminium from the skeleton. In this paper we present four chronic hemodialysis patients with aluminium toxicity and histologic osteomalacia in whom
changed. These observations are discussed with reference to the clinical, biochemical and bone histomorphometric findings.
the mineralization defect greatly regressed after the use of reverse osmosis treated—water for dialysis, but without further treatment. In three other patients, also with aluminium toxicity and histologic osteomalacia, similarly treated, the histological severity of the osteomalacia remained static. Those patients in whom bone mineralization status improved developed hyperparathyroidism after reverse osmosis water— treatment, whereas the static patients remained euparathyroid. The results suggest that resolution of alumium related osteomalacia may occur with reduction in dialysis fluid aluminium, and that parathyroid hormone plays a role in the healing of aluminium related osteomalacia. The therapeutic implications are twofold: (1) attempts to remove all traces of hyperparathyroidism may be detrimental to the bone mineralization status; and (2) stimulation of the parathyroid glands by means of a mild reduction in dialysis fluid calcium may be of value in the management of those cases with persistent osteomalacia and low bone turnover.
Methods
Patients Seven patients (4 males, 3 females, aged 29 to 64 years) with advanced chronic renal failure of various etiologies were studied. These were all of the patients on dialysis in our unit who
had clinical or histological evidence of aluminium toxicity before the introduction of reverse osmosis (RO) water—treat-
ment, and who had continued on dialysis for a sufficient duration to enable assessment of the histological response to
the introduction of RO water treatment. The patients had received regular hemodialysis at home or in the hospital for between 11 and 78 months before acquisition of a reverse
Aluminium is now considered to be the prime factor in the pathogenesis of dialysis osteomalacia affecting patients with chronic renal failure [1—6]. The major soure of the aluminium has been dialysis fluid [7—10], prepared directly from the domestic water supply to which aluminium sulphate has been added as a flocculating agent to remove brown particulate matter. The aluminium binds to the calcification front [11—13]
osmosis (RO) unit, during which time all patients in group 1 and patient 1 in group 2 used softened water, and patients 2 and 3 in group 2 had no water treatment. The water supply to all patients was treated with aluminium sulphate. Aluminium—containing
phosphate binders were prescribed if required to maintain
where it appears to inhibit mineralization of osteoid, and because skeletal uptake of calcium is blocked, there is a
serum inorganic phosphate below 2 mmol/liter throughout the period of observation and were continued during the period of reverse osmosis water—treatment. All patients had histologic evidence of osteomalacia associated with heavy deposition of aluminium at calcified bone-osteoid interfaces. As a result of the histologic findings in iliac crest bone biopsies obtained after the use of reverse osmosis water—treatment for three years, the patients were divided into group 1, comprising patients now without histologic osteomalacia and one patient with much less
tendency to hypercalcemia [5, 14] and relative hypoparathyroid-
ism. Because of low bone turnover and morbidity due to aluminium related anemia [15] and neurotoxicity [16], it has
been assumed that the prognosis is poor, although recently improvement in bone mineralization status has been reported severe osteomalacia, and group 2 which consisted of three after removal of aluminium from the dialysis water by reverse patients with unchanged skeletal pathology. The groups were compared using the Mann—Whitney U-test to determine any osmosis [14, 17, 18].
differences in mean plasma—aluminium levels, serum biochemistry and bone histomorphometric indices either before or after Received for publication April 1, 1985 and in revised form May 8 and November 21, 1986
the use of reverse osmosis. This non-parametric statistical model was employed because of the small sample size and
© 1987 by the International Society of Nephrology
unknown distribution types [19].
96
97
Aluminium—related osteomalacia
Table 1. Clinical and biochemical details of patients before RO water treatment Serum/plasma biochem istry
yr
Calcium mmol/liter
Phosphate mmol/liter
units/liter
Group 1 1 (JD) 2 (EW) 3 (iF) 4 (DM) Group 2
24 42 47 36
2.70 2.80 3.00 2.65
1.90 1.50 1.52 1.90
I (AD) 2 (MH)
59 64
1.77 1.50
3(RS) Normal range
63
2.99 2.60 2.55 2.16—2.62
0.80—1.40
Patients
Age
PC < 0.03
1.00
NSd
.
Dialysis fluid aluminium ,amol/liter
PTH pg/liter
Aluminium
80 78 96 95
0.86 NAb 2.40
12.8 13.4 5.1
NAC
34
2.64 0.52
3.30
9.8
2.27
28 47 27
99 60 75
0.26
8.1 12.4 18.4
NAC
APC
0.57 0.80
<1.00
<0.60
NS'1
0.05
mol/liter
2.3
2.3
—
— NDd
Months on dialysis
15 11
10
— <0.03
a Alkaline phosphatase b Not available C
d
Statistical comparisons are for group 1 vs. group 2, by the U-test of Mann—Whitney Not significant
C These patients were commenced on reverse osmosis water treatment prior to measurement of dialysis fluid aluminium but mean water aluminium for both patients was 7.1 mol/liter
linked to a microcomputer, a method broadly similar to that Plasma and dialysis fluid aluminium and serum levels of employed by Malluche et al [24], the following histomorphometric variables were measured for each biopsy: relative calcium, inorganic phosphate and alkaline phosphatase (AP) osteoid volume (OV) [25], total osteoid surface (OS) [25], the had been measured monthly in each patient prior to the use of reverse osmosis and during the period of reverse osmosis proportion of OS bearing a calcification front (CF) [22], active water—treatment and were expressed as mean pre-RO values. osteoblastic surface (AOS) [251 and active resorption surface Aluminium concentrations were estimated by means of electro- (ARS) [26]. The width of the thickest osteoid seam was exthermal atomic—absorption spectrophotometry as described pressed as the maximum number of bright osteoid lamellae visualized under polarised light. previously [20]. Serum calcium, inorganic phosphate and alka- (MNOL) The values obtained for OV, OS, CF and MNOL were line phosphatase were assayed by standard laboratory techniques. Serum PTH was measured on a few occasions only, employed as indicators of the presence and severity of around the times of the bone biopsies, by a double antibody osteomalacia. A diagnosis of osteomalacia was made in those radioimmunoassay using rabbit anti-PTH serum directed pre- biopsy specimens with MNOL >4 and CF <60% [22]. The values obtained for AOS and ARS were regarded as indices of dominantly against the N-terminal sequence of PTH. the degree of secondary hyperparathyroidism. Biochemistry
Bone biopsies
Results
Iliac crest bone biopsy—specimens were obtained from each patient shortly before acquisition of a reverse osmosis unit and after three years of water treatment. Pre-RO bone biopsies were performed using a trephine bone—marrow needle providing a
Before the introduction of reverse osmosis
phosphate—buffered formaldehyde and embedded in methacryl-
phosphate and alkaline phosphatase. Serum PTH tended to be
The patients of group 1 were younger and had been on core of bone 15 x 3 mm; post-RO transiliac bone biopsy dialysis for longer than those of group 2 (Table 1). There was no specimens (8 mm diameter) were obtained by the Meunier difference between the groups with regard to plasma and needle. All biopsy specimens were fixed in 4% neutral dialysis fluid aluminium or serum levels of calcium, inorganic ate; from each biopsy specimen thin (5 m) undecalcified higher in group 1. Dialysis fluid aluminium was high in four sections were cut on a Jung K sledge microtome. Three patients, and likely to have been high in a further two patients representative sections from each biopsy specimen were on the basis of very high water—aluminium. In one patient stained with Goidner's technique [21] for quantitative histology, and from each of the post-RO biopsy specimens, the immedi-
(patient 3 of group 1) dialysis fluid aluminium was not high, but
he had been on dialysis for four years and dialysis fluid
ately adjacent sections were stained with toluidine blue for aluminium measurements were available for only a few months estimation of the extent of surface osteoid bearing a calcifica- prior to the use of reverse osmosis. Fracturing osteodystrophy tion front [22]. The "Aluminon" method [23] was utilized for was present in two patients in group 1, (fractured scapula and detection of aluminium. ribs in patients 1 and 2) and one patient in group 2 (fractured By means of a semiautomatic method using the Graphic neck of femur and pubic ramus in patient 1). Patient 1 in group Digitising System 1 equipment (Graphic Information Services 2 also had dialysis encephalopathy and all patients except Ltd) which comprised a digitizing board with electronic cursor patient 4 in group 1 had a microcytic anemia.
Smith et a!
98 Relative osteoid volume %
MNOL
pre-R.0. post-R.0.
pre-R.0. post-R.0.
30
Total osteoid surface %
12
•
Calcification
front % post-R.0.
pre-R.0. post-R.0.
•
70
S
•
80
•
S
60 9
• o
20
0
o
• 10
• •
6
0
—
--
_&
•
3
NS
NS
-I5
o
Fig. 1. Bone histomorphometry indicating the severity of osteomalacia and its response to RO water treatment. Symbols are: (•) Group 1 patients, (0) group 2 patients. P statistical comparisons are from group 1 vs. group 2 by the Mann—Whitney U-test. Bars indicate the upper limit of the normal range for relative osteoid volume, maximum number of osteoid lamellae (MNOL) and total osteoid surface. The lower limit of the normal range for the extent of calcification fronts along total osteoid surfaces is indicated by the bar at 60%.
0
40
o
• •
40
0
20 0
0 o
20
0 NS
0 o
0
<0.03
<0.03
<0.03
NS
Active
Active resorption
osteoblastic surface %
surface %
pre-R.0.
20
601
•
10
0
p
.
-•5-
•
0
•
50
30
0
0
•
•
S
pre-R.0.
post-R.0.
$
post-R.0.
.
20
15
.
15
10
0
. 5
. .
.
.
10
.
0
0
5
8
0
0
p
NS
<0.03
p
NS
Histologically, all seven patients had moderately severe osteomalacia characterized by an increase in MNOL and OV, there being no differences in these parameters between the two groups (Fig. 1). A calcification front could not be detected by toluidine blue in any of the biopsies. Whereas the mineralization deficit was extensive in group 1 (OS > 48%), the patients in group 2 had a more focal form of osteomalacia (OS < 32%). In all cases, strongly positive Aluminon staining was demonstrated along most of the length of the calcified bone—osteoid interface. As well as osteomalacia, all seven patients had mild
<0.03
Fig. 2. Bone histomorphometry indicating the degree of hyperparathyroidism before and after RD water treatment. Symbols are: (•) Group 1 patients, (0) group 2 patients. P statistical comparisons are from group 1 vs. group 2 by the Mann—Whitney U-test. Bars indicate the upper limit of the normal ranges.
osteitis fibrosa (hyperparathyroid bone disease), expressed as a mild increase in active resorption surface with deep Howship's
lacunae and mild focal fibrosis not exceeding grade 2 [27]; active osteoblastic surfaces were increased in only two patients. The two groups did not differ in the degree of hyperparathyroidism (Fig. 2).
After the introduction of reverse osmosis With reverse osmosis water—treatment there was a significant
reduction in both plasma and dialysis fluid aluminium in both
99
Aluminium—related osteomalacia
Table 2. Clinical a nd biochemical details of patients after RO water treatment Serum/plasma biochemistry Patients Group 1 I (JD) 2 (EW) 3 (JF) 4 (DM) Group 2 I (AD) 2 (MH) 3 (RS) Normal range
Calcium mmol/liter
Phosphate mmol/liter
27 45 50 39
2.33 2.83
1.62 1.80 1.64
2.70
2.78
62 67 66
2.67 2.30 2.38
0.90
2.16—2.62
0.80—1.40
Age
yr
—
2.35
NS
P"
1.60 1.23
<0.03
AP units/liter 125 138
239 180
•
PTH pg/liter
Aluminium pinol/liter
Dialysis fluid aluminium pinol/liter
1.50
6.3 3.4 5.0 8.3
0.33 0.6 0.54
2.30 2.70 2.60
71
0.34 0.58 0.47
<100 <0.03
<0.60 <0.03
60 64
6.3 7.3
5.5 —
1.18
0.6 0.4 0.4 —
NSC
O Alkaline phosphatase b Statistical comparisons are for group 1 vs. group 2, by the U-test of Mann-Whitney C
Not significant
groups, and there was again no difference between the groups. However, the plasma aluminium remained significantly elevated in most patients. The serum calcium was similar in both groups, but the serum phosphate in the patients of group 1 was significantly greater than in those of group 2. The patients of group 1 exhibited biochemical evidence of hyperparathyroidism with elevated serum levels of alkaline phosphatase and PTH whereas those in group 2 did not; the differences were significant (Table 2). Healing of fractures occurred in all patients with fracturing bone disease before the introduction of reverse osmosis and no
study. While the mineralization defect eventually resolved in one of the patients of Boyce et a! [141 with aluminium related osteomalacia after removal from exposure to aluminium, one of
patient developed new fractures. This was accompanied by resolution of microcytosis and improvement in anemia, but patient 1 in group 2 subsequently died of dialysis encephalopathy.
repsonse could not be distinguished on the basis of bone
Histologically, three of the patients in group 1 no longer had
the two patients with fracturing osteomalacia reported by Brown et al [181 failed to respond to RO water purification alone, although was later successfully treated by desferrioxamine. Our results indicate that, while a good clinical response with healing of fractures may occur following the introduction of RO water treatment, this is not always accompanied by histological
resolution of osteomalacia. Patients with a good histological histology or routine serum biochemistry before the use of RO water treatment. Both groups had been exposed to high levels of aluminium in the dialysis fluid with very high plasma— aluminium levels which were similar in both groups. Following
osteomalacia (MNOL <5, CF >60%) and the fourth patient the introduction of RO water treatment the dialysis fluid showed substantial improvement in bone mineralization, with aluminium was maintained at a low level in both groups and reduction in OV from 21.2% to 11.4% and reduction of MNOL there was a significant fall in plasma aluminium. However, the from 9 to 6 (Fig. 1). By contrast, the degree of osteomalacia plasma aluminium remained significantly elevated in most paaffecting those patients of group 2 was unchanged with respect tients and was higher than we would expect to result from the to the previous biopsies. In six patients, weakly—positive continuation of small doses of aluminium—containing phosphate Aluminon staining was distributed focally along the length of binding agents. This response confirms our previous observathe calcified bone—osteoid interface and occasionally at cement tion that the plasma aluminium falls only slowly following lines within calcified bone; in the seventh patient (from group 1) reduction in exposure to aluminium, presumably as a result of aluminium could not be shown histochemically. After reverse poor clearance during hemodialysis and relatively slow uptake osmosis water—treatment the patients in group 1 had more by tissues [291. We did not assess the bone apposition rate in our patients advanced osteitis fibrosa reflected histomorphometrically by significantly—increased active resorption and active osteoblastic using double tetracycline labelling, but there was a marked rise surfaces, whereas in group 2 the degree of osteitis fibrosa in the percentage of osteoid seams bearing a calcification front in all patients with RO water treatment, the rise being signifiremained mild (Fig. 2).
cantly higher in patients in group 1. This, together with the striking reduction in indices of osteoid bone volume in the Although the studies of McClure et al [26, 281 indicate that patients in group 1, despite increased bone turnover, is strong introduction of RO water treatment was associated with an indirect evidence that there was an improvement in bone Discussion
improvement in bone mineralization status, they do not specifically refer to the progress of individual patients. Leather et al [17] reported that fractures in their renal osteodystrophy cases usually healed following the use of a deionizer to prepare the dialysis fluid, but they did not include bone histology in their
mineralization. The main distinguishing feature of the patients with a good
histological response to RO water treatment was that they tended to have higher serum PTH levels. It is interesting to note that they were younger and had been on hemodialysis for longer
100
Smith et a!
inorganic phosphate were not involved in the genesis of postRO hyperparathyroidism, the presence of raised serum, and therefore extracellular fluid levels would augment the calcium— hyperplasia, and the parathyroid glands of the responders, phosphate ion product in osteoid and counteract any possible exposed to abnormal mineral biochemistry for longer periods of localized phosphate depleting effect of aluminium [38, 39]. Two main points emerge from this study. First, aluminium time than the nonresponders, have had more opportunity to develop hyperplasia. After the introduction of RO units, those related osteomalacia may persist in chronic hemodialysis papatients with persistent osteomalacia remained biochemically tients with low bone turnover despite a large reduction in euparathyroid and only had mild osteitis fibrosa, whereas the plasma aluminium. Although it is good policy to attempt to keep responders developed biochemical and histologic evidence of serum inorganic phosphate within reasonable limits to prevent hyperparathyroidism consistent with removal of aluminium— metastatic calcification in soft tissue [40], we consider it possimediated suppression of PTH release from already hyperplastic bly detrimental to the bone mineralization status to manipulate glands. Furthermore, the results suggest that PTH could be serum levels of calcium and inorganic phosphate or to perform involved in the restoration of mineralization in "paralyzed" parathyroidectomy in order to remove all traces of hyperparaosteoid seams, possible through the genesis of matrix vesicles thyroidism. Although it is generally accepted that osteomalacia by PTH-activated osteoblasts. Although it is likely that matrix is the crippling form of renal osteodystrophy, in our experience vesicles are not involved in mineralization of lamellar bone mild to moderate osteitis fibrosa is rarely symptomatic and under normal circumstances [31], Anderson et al [321 identified therefore is clinically acceptable. Secondly, aluminium related osteomalacia will respond to matrix vesicles and associated tiny clusters of apatite—like material in osteoid seams subjacent to active osteoblasts in six RO water treatment alone, but a good histological response out of seven patients with renal osteodystrophy. While calcium occurs only in the presence of hyperparathyroidism. In those hydroxyapatite crystal formation at the calcification front ap- cases with persistent osteomalacia and low bone turnover, a pears to be blocked by aluminium [11—13], possibly acting as a mild reduction in dialysis fluid calcium with the aim of stimucrystal poison [33], matrix vesicles derived from osteoblasts lating the parathyroid glands may offer a useful adjunct or reactivated by high PTH levels could serve to nucleate a new alternative to desferrioxamine in the management of this discalcification front in the osteoid seam superficial to the tressing disease.
than the nonresponders, While aluminium appears to suppress parathyroid hormone release [301 there is currently no evidence that the element can inhibit the development of parathyroid
aluminium—saturated calcified bone—osteoid interface, with sub-
sequent mineralization of the seam. This mechanism of bypass-
Reprint requests to Dr. G.D. Smith, Department of Pathology,
ing the aluminium barrier is not available to euparathyroid Stobhill General Hospital, Glasgow G21 3UW, United Kingdom. patients whose inactive osteoblasts were unable to provide References matrix vesicles. While the similar aluminium staining on our two groups after RO water treatment may simply reflect quantitative limitations of the staining method, this might also be explained by PTH-induced mineralization in a new calcification
front. This hypothesis is consistent with the observation by Cournot—Witmer et al [12] that moderate to severe hyperparathyroidism appeared to protect against osteomalacia despite the
HA, MCCARTHY JH, HERRINGTON J: Bone aluminium in haemodialysis patients and in rats injected with aluminium chloride: Relationship to impaired bone mineralisation. J Clin Pathol
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a role of relative hypoparathyroidism in the pathogenesis of aluminium related osteomalacia [6, 12, 34, 351, and the occurrence of osteomalacia after parathyroidectomy further supports the role of PTH in maintaining bone mineralization in uremia [36]. Although it has been implied that the protective effect of high serum PTH levels is mediated via high bone turnover with dilution of the bone surface aluminium—concentration [3], we
consider this hypothesis unlikely because the two groups of patients in our study did not differ in plasma aluminium levels or, by assumption, in aluminium levels at the bone surface. In addition, bone aluminium staining after RO water treatment was similar in both groups.
After RO water purification, the group in which the bone mineralization status improved had higher serum levels of
4.
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1969
Aluminium—related osteomalacia: Response to reverse osmosis water treatment GEORGE D. SMITH, ROBIN J. WINNEY, ALEXANDER MCLEAN, and JAMES S. ROBSON Department of Pathology, University Medical School, and Medical Renal Unit, Royal Infirmary, Edinburgh, Scotland, United Kingdom
In this paper we described seven chronic-hemodialysis patients with aluminium related osteomalacia who were subsethereby inhibiting mineralization of osteoid. Because this form of quently provided with reverse osmosis facilities, but had no osteomalacia is vitamin D resistant, the condition has often been other alteration in management. After three years, four patients
Aluminium—related osteomalacia: response to reverse osmosis water treatment. It is generally accepted that aluminium induces osteomalacia in chronic hemodialysis patients by binding to the calcification front,
showed a marked improvement in bone mineralization, whereas
assumed to be irreversible, although promising results have been
in the other three patients the skeletal pathology was un-
achieved recently by using a chelating agent for removal of aluminium from the skeleton. In this paper we present four chronic hemodialysis patients with aluminium toxicity and histologic osteomalacia in whom
changed. These observations are discussed with reference to the clinical, biochemical and bone histomorphometric findings.
the mineralization defect greatly regressed after the use of reverse osmosis treated—water for dialysis, but without further treatment. In three other patients, also with aluminium toxicity and histologic osteomalacia, similarly treated, the histological severity of the osteomalacia remained static. Those patients in whom bone mineralization status improved developed hyperparathyroidism after reverse osmosis water— treatment, whereas the static patients remained euparathyroid. The results suggest that resolution of alumium related osteomalacia may occur with reduction in dialysis fluid aluminium, and that parathyroid hormone plays a role in the healing of aluminium related osteomalacia. The therapeutic implications are twofold: (1) attempts to remove all traces of hyperparathyroidism may be detrimental to the bone mineralization status; and (2) stimulation of the parathyroid glands by means of a mild reduction in dialysis fluid calcium may be of value in the management of those cases with persistent osteomalacia and low bone turnover.
Methods
Patients Seven patients (4 males, 3 females, aged 29 to 64 years) with advanced chronic renal failure of various etiologies were studied. These were all of the patients on dialysis in our unit who
had clinical or histological evidence of aluminium toxicity before the introduction of reverse osmosis (RO) water—treat-
ment, and who had continued on dialysis for a sufficient duration to enable assessment of the histological response to
the introduction of RO water treatment. The patients had received regular hemodialysis at home or in the hospital for between 11 and 78 months before acquisition of a reverse
Aluminium is now considered to be the prime factor in the pathogenesis of dialysis osteomalacia affecting patients with chronic renal failure [1—6]. The major soure of the aluminium has been dialysis fluid [7—10], prepared directly from the domestic water supply to which aluminium sulphate has been added as a flocculating agent to remove brown particulate matter. The aluminium binds to the calcification front [11—13]
osmosis (RO) unit, during which time all patients in group 1 and patient 1 in group 2 used softened water, and patients 2 and 3 in group 2 had no water treatment. The water supply to all patients was treated with aluminium sulphate. Aluminium—containing
phosphate binders were prescribed if required to maintain
where it appears to inhibit mineralization of osteoid, and because skeletal uptake of calcium is blocked, there is a
serum inorganic phosphate below 2 mmol/liter throughout the period of observation and were continued during the period of reverse osmosis water—treatment. All patients had histologic evidence of osteomalacia associated with heavy deposition of aluminium at calcified bone-osteoid interfaces. As a result of the histologic findings in iliac crest bone biopsies obtained after the use of reverse osmosis water—treatment for three years, the patients were divided into group 1, comprising patients now without histologic osteomalacia and one patient with much less
tendency to hypercalcemia [5, 14] and relative hypoparathyroid-
ism. Because of low bone turnover and morbidity due to aluminium related anemia [15] and neurotoxicity [16], it has
been assumed that the prognosis is poor, although recently improvement in bone mineralization status has been reported severe osteomalacia, and group 2 which consisted of three after removal of aluminium from the dialysis water by reverse patients with unchanged skeletal pathology. The groups were compared using the Mann—Whitney U-test to determine any osmosis [14, 17, 18].
differences in mean plasma—aluminium levels, serum biochemistry and bone histomorphometric indices either before or after Received for publication April 1, 1985 and in revised form May 8 and November 21, 1986
the use of reverse osmosis. This non-parametric statistical model was employed because of the small sample size and
© 1987 by the International Society of Nephrology
unknown distribution types [19].
96
97
Aluminium—related osteomalacia
Table 1. Clinical and biochemical details of patients before RO water treatment Serum/plasma biochem istry
yr
Calcium mmol/liter
Phosphate mmol/liter
units/liter
Group 1 1 (JD) 2 (EW) 3 (iF) 4 (DM) Group 2
24 42 47 36
2.70 2.80 3.00 2.65
1.90 1.50 1.52 1.90
I (AD) 2 (MH)
59 64
1.77 1.50
3(RS) Normal range
63
2.99 2.60 2.55 2.16—2.62
0.80—1.40
Patients
Age
PC < 0.03
1.00
NSd
.
Dialysis fluid aluminium ,amol/liter
PTH pg/liter
Aluminium
80 78 96 95
0.86 NAb 2.40
12.8 13.4 5.1
NAC
34
2.64 0.52
3.30
9.8
2.27
28 47 27
99 60 75
0.26
8.1 12.4 18.4
NAC
APC
0.57 0.80
<1.00
<0.60
NS'1
0.05
mol/liter
2.3
2.3
—
— NDd
Months on dialysis
15 11
10
— <0.03
a Alkaline phosphatase b Not available C
d
Statistical comparisons are for group 1 vs. group 2, by the U-test of Mann—Whitney Not significant
C These patients were commenced on reverse osmosis water treatment prior to measurement of dialysis fluid aluminium but mean water aluminium for both patients was 7.1 mol/liter
linked to a microcomputer, a method broadly similar to that Plasma and dialysis fluid aluminium and serum levels of employed by Malluche et al [24], the following histomorphometric variables were measured for each biopsy: relative calcium, inorganic phosphate and alkaline phosphatase (AP) osteoid volume (OV) [25], total osteoid surface (OS) [25], the had been measured monthly in each patient prior to the use of reverse osmosis and during the period of reverse osmosis proportion of OS bearing a calcification front (CF) [22], active water—treatment and were expressed as mean pre-RO values. osteoblastic surface (AOS) [251 and active resorption surface Aluminium concentrations were estimated by means of electro- (ARS) [26]. The width of the thickest osteoid seam was exthermal atomic—absorption spectrophotometry as described pressed as the maximum number of bright osteoid lamellae visualized under polarised light. previously [20]. Serum calcium, inorganic phosphate and alka- (MNOL) The values obtained for OV, OS, CF and MNOL were line phosphatase were assayed by standard laboratory techniques. Serum PTH was measured on a few occasions only, employed as indicators of the presence and severity of around the times of the bone biopsies, by a double antibody osteomalacia. A diagnosis of osteomalacia was made in those radioimmunoassay using rabbit anti-PTH serum directed pre- biopsy specimens with MNOL >4 and CF <60% [22]. The values obtained for AOS and ARS were regarded as indices of dominantly against the N-terminal sequence of PTH. the degree of secondary hyperparathyroidism. Biochemistry
Bone biopsies
Results
Iliac crest bone biopsy—specimens were obtained from each patient shortly before acquisition of a reverse osmosis unit and after three years of water treatment. Pre-RO bone biopsies were performed using a trephine bone—marrow needle providing a
Before the introduction of reverse osmosis
phosphate—buffered formaldehyde and embedded in methacryl-
phosphate and alkaline phosphatase. Serum PTH tended to be
The patients of group 1 were younger and had been on core of bone 15 x 3 mm; post-RO transiliac bone biopsy dialysis for longer than those of group 2 (Table 1). There was no specimens (8 mm diameter) were obtained by the Meunier difference between the groups with regard to plasma and needle. All biopsy specimens were fixed in 4% neutral dialysis fluid aluminium or serum levels of calcium, inorganic ate; from each biopsy specimen thin (5 m) undecalcified higher in group 1. Dialysis fluid aluminium was high in four sections were cut on a Jung K sledge microtome. Three patients, and likely to have been high in a further two patients representative sections from each biopsy specimen were on the basis of very high water—aluminium. In one patient stained with Goidner's technique [21] for quantitative histology, and from each of the post-RO biopsy specimens, the immedi-
(patient 3 of group 1) dialysis fluid aluminium was not high, but
he had been on dialysis for four years and dialysis fluid
ately adjacent sections were stained with toluidine blue for aluminium measurements were available for only a few months estimation of the extent of surface osteoid bearing a calcifica- prior to the use of reverse osmosis. Fracturing osteodystrophy tion front [22]. The "Aluminon" method [23] was utilized for was present in two patients in group 1, (fractured scapula and detection of aluminium. ribs in patients 1 and 2) and one patient in group 2 (fractured By means of a semiautomatic method using the Graphic neck of femur and pubic ramus in patient 1). Patient 1 in group Digitising System 1 equipment (Graphic Information Services 2 also had dialysis encephalopathy and all patients except Ltd) which comprised a digitizing board with electronic cursor patient 4 in group 1 had a microcytic anemia.
Smith et a!
98 Relative osteoid volume %
MNOL
pre-R.0. post-R.0.
pre-R.0. post-R.0.
30
Total osteoid surface %
12
•
Calcification
front % post-R.0.
pre-R.0. post-R.0.
•
70
S
•
80
•
S
60 9
• o
20
0
o
• 10
• •
6
0
—
--
_&
•
3
NS
NS
-I5
o
Fig. 1. Bone histomorphometry indicating the severity of osteomalacia and its response to RO water treatment. Symbols are: (•) Group 1 patients, (0) group 2 patients. P statistical comparisons are from group 1 vs. group 2 by the Mann—Whitney U-test. Bars indicate the upper limit of the normal range for relative osteoid volume, maximum number of osteoid lamellae (MNOL) and total osteoid surface. The lower limit of the normal range for the extent of calcification fronts along total osteoid surfaces is indicated by the bar at 60%.
0
40
o
• •
40
0
20 0
0 o
20
0 NS
0 o
0
<0.03
<0.03
<0.03
NS
Active
Active resorption
osteoblastic surface %
surface %
pre-R.0.
20
601
•
10
0
p
.
-•5-
•
0
•
50
30
0
0
•
•
S
pre-R.0.
post-R.0.
$
post-R.0.
.
20
15
.
15
10
0
. 5
. .
.
.
10
.
0
0
5
8
0
0
p
NS
<0.03
p
NS
Histologically, all seven patients had moderately severe osteomalacia characterized by an increase in MNOL and OV, there being no differences in these parameters between the two groups (Fig. 1). A calcification front could not be detected by toluidine blue in any of the biopsies. Whereas the mineralization deficit was extensive in group 1 (OS > 48%), the patients in group 2 had a more focal form of osteomalacia (OS < 32%). In all cases, strongly positive Aluminon staining was demonstrated along most of the length of the calcified bone—osteoid interface. As well as osteomalacia, all seven patients had mild
<0.03
Fig. 2. Bone histomorphometry indicating the degree of hyperparathyroidism before and after RD water treatment. Symbols are: (•) Group 1 patients, (0) group 2 patients. P statistical comparisons are from group 1 vs. group 2 by the Mann—Whitney U-test. Bars indicate the upper limit of the normal ranges.
osteitis fibrosa (hyperparathyroid bone disease), expressed as a mild increase in active resorption surface with deep Howship's
lacunae and mild focal fibrosis not exceeding grade 2 [27]; active osteoblastic surfaces were increased in only two patients. The two groups did not differ in the degree of hyperparathyroidism (Fig. 2).
After the introduction of reverse osmosis With reverse osmosis water—treatment there was a significant
reduction in both plasma and dialysis fluid aluminium in both
99
Aluminium—related osteomalacia
Table 2. Clinical a nd biochemical details of patients after RO water treatment Serum/plasma biochemistry Patients Group 1 I (JD) 2 (EW) 3 (JF) 4 (DM) Group 2 I (AD) 2 (MH) 3 (RS) Normal range
Calcium mmol/liter
Phosphate mmol/liter
27 45 50 39
2.33 2.83
1.62 1.80 1.64
2.70
2.78
62 67 66
2.67 2.30 2.38
0.90
2.16—2.62
0.80—1.40
Age
yr
—
2.35
NS
P"
1.60 1.23
<0.03
AP units/liter 125 138
239 180
•
PTH pg/liter
Aluminium pinol/liter
Dialysis fluid aluminium pinol/liter
1.50
6.3 3.4 5.0 8.3
0.33 0.6 0.54
2.30 2.70 2.60
71
0.34 0.58 0.47
<100 <0.03
<0.60 <0.03
60 64
6.3 7.3
5.5 —
1.18
0.6 0.4 0.4 —
NSC
O Alkaline phosphatase b Statistical comparisons are for group 1 vs. group 2, by the U-test of Mann-Whitney C
Not significant
groups, and there was again no difference between the groups. However, the plasma aluminium remained significantly elevated in most patients. The serum calcium was similar in both groups, but the serum phosphate in the patients of group 1 was significantly greater than in those of group 2. The patients of group 1 exhibited biochemical evidence of hyperparathyroidism with elevated serum levels of alkaline phosphatase and PTH whereas those in group 2 did not; the differences were significant (Table 2). Healing of fractures occurred in all patients with fracturing bone disease before the introduction of reverse osmosis and no
study. While the mineralization defect eventually resolved in one of the patients of Boyce et a! [141 with aluminium related osteomalacia after removal from exposure to aluminium, one of
patient developed new fractures. This was accompanied by resolution of microcytosis and improvement in anemia, but patient 1 in group 2 subsequently died of dialysis encephalopathy.
repsonse could not be distinguished on the basis of bone
Histologically, three of the patients in group 1 no longer had
the two patients with fracturing osteomalacia reported by Brown et al [181 failed to respond to RO water purification alone, although was later successfully treated by desferrioxamine. Our results indicate that, while a good clinical response with healing of fractures may occur following the introduction of RO water treatment, this is not always accompanied by histological
resolution of osteomalacia. Patients with a good histological histology or routine serum biochemistry before the use of RO water treatment. Both groups had been exposed to high levels of aluminium in the dialysis fluid with very high plasma— aluminium levels which were similar in both groups. Following
osteomalacia (MNOL <5, CF >60%) and the fourth patient the introduction of RO water treatment the dialysis fluid showed substantial improvement in bone mineralization, with aluminium was maintained at a low level in both groups and reduction in OV from 21.2% to 11.4% and reduction of MNOL there was a significant fall in plasma aluminium. However, the from 9 to 6 (Fig. 1). By contrast, the degree of osteomalacia plasma aluminium remained significantly elevated in most paaffecting those patients of group 2 was unchanged with respect tients and was higher than we would expect to result from the to the previous biopsies. In six patients, weakly—positive continuation of small doses of aluminium—containing phosphate Aluminon staining was distributed focally along the length of binding agents. This response confirms our previous observathe calcified bone—osteoid interface and occasionally at cement tion that the plasma aluminium falls only slowly following lines within calcified bone; in the seventh patient (from group 1) reduction in exposure to aluminium, presumably as a result of aluminium could not be shown histochemically. After reverse poor clearance during hemodialysis and relatively slow uptake osmosis water—treatment the patients in group 1 had more by tissues [291. We did not assess the bone apposition rate in our patients advanced osteitis fibrosa reflected histomorphometrically by significantly—increased active resorption and active osteoblastic using double tetracycline labelling, but there was a marked rise surfaces, whereas in group 2 the degree of osteitis fibrosa in the percentage of osteoid seams bearing a calcification front in all patients with RO water treatment, the rise being signifiremained mild (Fig. 2).
cantly higher in patients in group 1. This, together with the striking reduction in indices of osteoid bone volume in the Although the studies of McClure et al [26, 281 indicate that patients in group 1, despite increased bone turnover, is strong introduction of RO water treatment was associated with an indirect evidence that there was an improvement in bone Discussion
improvement in bone mineralization status, they do not specifically refer to the progress of individual patients. Leather et al [17] reported that fractures in their renal osteodystrophy cases usually healed following the use of a deionizer to prepare the dialysis fluid, but they did not include bone histology in their
mineralization. The main distinguishing feature of the patients with a good
histological response to RO water treatment was that they tended to have higher serum PTH levels. It is interesting to note that they were younger and had been on hemodialysis for longer
100
Smith et a!
inorganic phosphate were not involved in the genesis of postRO hyperparathyroidism, the presence of raised serum, and therefore extracellular fluid levels would augment the calcium— hyperplasia, and the parathyroid glands of the responders, phosphate ion product in osteoid and counteract any possible exposed to abnormal mineral biochemistry for longer periods of localized phosphate depleting effect of aluminium [38, 39]. Two main points emerge from this study. First, aluminium time than the nonresponders, have had more opportunity to develop hyperplasia. After the introduction of RO units, those related osteomalacia may persist in chronic hemodialysis papatients with persistent osteomalacia remained biochemically tients with low bone turnover despite a large reduction in euparathyroid and only had mild osteitis fibrosa, whereas the plasma aluminium. Although it is good policy to attempt to keep responders developed biochemical and histologic evidence of serum inorganic phosphate within reasonable limits to prevent hyperparathyroidism consistent with removal of aluminium— metastatic calcification in soft tissue [40], we consider it possimediated suppression of PTH release from already hyperplastic bly detrimental to the bone mineralization status to manipulate glands. Furthermore, the results suggest that PTH could be serum levels of calcium and inorganic phosphate or to perform involved in the restoration of mineralization in "paralyzed" parathyroidectomy in order to remove all traces of hyperparaosteoid seams, possible through the genesis of matrix vesicles thyroidism. Although it is generally accepted that osteomalacia by PTH-activated osteoblasts. Although it is likely that matrix is the crippling form of renal osteodystrophy, in our experience vesicles are not involved in mineralization of lamellar bone mild to moderate osteitis fibrosa is rarely symptomatic and under normal circumstances [31], Anderson et al [321 identified therefore is clinically acceptable. Secondly, aluminium related osteomalacia will respond to matrix vesicles and associated tiny clusters of apatite—like material in osteoid seams subjacent to active osteoblasts in six RO water treatment alone, but a good histological response out of seven patients with renal osteodystrophy. While calcium occurs only in the presence of hyperparathyroidism. In those hydroxyapatite crystal formation at the calcification front ap- cases with persistent osteomalacia and low bone turnover, a pears to be blocked by aluminium [11—13], possibly acting as a mild reduction in dialysis fluid calcium with the aim of stimucrystal poison [33], matrix vesicles derived from osteoblasts lating the parathyroid glands may offer a useful adjunct or reactivated by high PTH levels could serve to nucleate a new alternative to desferrioxamine in the management of this discalcification front in the osteoid seam superficial to the tressing disease.
than the nonresponders, While aluminium appears to suppress parathyroid hormone release [301 there is currently no evidence that the element can inhibit the development of parathyroid
aluminium—saturated calcified bone—osteoid interface, with sub-
sequent mineralization of the seam. This mechanism of bypass-
Reprint requests to Dr. G.D. Smith, Department of Pathology,
ing the aluminium barrier is not available to euparathyroid Stobhill General Hospital, Glasgow G21 3UW, United Kingdom. patients whose inactive osteoblasts were unable to provide References matrix vesicles. While the similar aluminium staining on our two groups after RO water treatment may simply reflect quantitative limitations of the staining method, this might also be explained by PTH-induced mineralization in a new calcification
front. This hypothesis is consistent with the observation by Cournot—Witmer et al [12] that moderate to severe hyperparathyroidism appeared to protect against osteomalacia despite the
HA, MCCARTHY JH, HERRINGTON J: Bone aluminium in haemodialysis patients and in rats injected with aluminium chloride: Relationship to impaired bone mineralisation. J Clin Pathol
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a role of relative hypoparathyroidism in the pathogenesis of aluminium related osteomalacia [6, 12, 34, 351, and the occurrence of osteomalacia after parathyroidectomy further supports the role of PTH in maintaining bone mineralization in uremia [36]. Although it has been implied that the protective effect of high serum PTH levels is mediated via high bone turnover with dilution of the bone surface aluminium—concentration [3], we
consider this hypothesis unlikely because the two groups of patients in our study did not differ in plasma aluminium levels or, by assumption, in aluminium levels at the bone surface. In addition, bone aluminium staining after RO water treatment was similar in both groups.
After RO water purification, the group in which the bone mineralization status improved had higher serum levels of
4.
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