Biomedical subjects
Publications and source records attributed to M K Ward.
A survey of 1293 patients in eighteen dialysis centres in Great Britain showed a highly significant rank correlation of the incidence of both fracturing dialysis osteodystrophy (osteomalacic dialysis osteodystrophy) and dialysis encephalopathy with the aluminium content of water used to prepare dialysate.
There is increasing evidence that aluminium accumulation in patients with impaired renal function has pathological consequences. The serum aluminium content of 45 patients with chronic renal failure was found to be significantly elevated when compared with normal subjects. A further rise in serum aluminium concentration was seen in patients with chronic renal failure when they were taking aluminium-containing phosphate binding agents. Patients with stable but moderately impaired renal function who are taking aluminium-containing phosphate binders for several years may be at risk from aluminium accumulation and the development of osteomalacia and encephalopathy as seen in patients on intermittent haemodialysis.
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Brain-aluminium concentrations were found to be significantly higher in 7 patients dying with dialysis encephalopathy (mean 15.9 microgram aluminium/g dry weight) than in 11 dialysed controls (4.4 microgram/g) and in 2 uraemic patients who were not dialysed (2.7 microgram/g). The grey matter from the patients with dialysis encephalopathy contained about three times as much aluminium as white matter. The results suggest that dialysis with untreated and/or softened tap-water (aluminium concentration 0.1-1.2 mg/1) makes the major contribution to brain-aluminium levels; dialysis with deionised water (aluminium concentration normally less than 0.02 mg/1) and intake of phosphate-binding AL(OH)3 gel are less important. Brain aluminium levels remain elevated for up to four years after restoration of good renal function by transplantation. The association of dialysis encephalopathy with high levels of aluminium in the brain and in the dialysis water emphasises the potential neurotoxicity of aluminium in man.
Four hundred and eighteen measurements of serum ionised calcium, total calcium, and protein concentrations were made from 47 normal volunteers, 104 patients with chronic renal failure (33 being treated conservatively and 71 with regular haemodialysis), and 83 renal transplant recipients. The serum ionised calcium concentration was measured with an Orion SS-20 meter and calculated from the total serum calcium and protein concentrations by using three formulae and a nomogram. In the normal subjects and patients undergoing regular haemodialysis, whose serum calcium concentrations were in or near the normal range, three of the calculations gave results similar to those obtained by direct measurement. In patients with conservatively treated chronic renal failure and those who had received renal transplants, however, there was poor aggrement between the methods. When patients with hypercalcaemia and hypocalcaemia from all the groups were considered separately there was again poor agreement between calculated and measured concentrations of serum ionised calcium. Of the patients whose measured concentrations of serum ionised calcium were high, 69-76% were classified as normal by the four indirect methods. We conclude that calculation of the serum ionised calcium concentrations is not an adequate substitute for direct measurement.
In patients maintained on regular haemodialysis in Newcastle upon Tyne the development of osteomalacia is substantially reduced when water used to prepare dialysate is deionised. After 1--4 years of dialysis, osteomalacia was evident in 15% of patients on deionised water in 70% of patients on softened water from the same source. The close association of dialysis encephalopathy and osteomalacia suggests a common aetiology. Both diseases occur in centres with a high tap-water aluminium content. Serum-aluminium concentrations were raised in patients undergoing regular haemodialysis in the Northern Region of England. Those using softened water had higher concentrations than those using deionised water. Patients on softened water who had encephalopathy or dementia had serum-aluminium concentrations similar to those of patients using the same water-supplies without symptoms of these diseases, but they had been treated for longer. The evidence that aluminium absorption from dialysate causes osteomalacia and encephalopathy is strong enough to justify the expense of treating water by deionisation, reverse osmosis, or both in centres where tap-water aluminium is high.
In a dialysis centre with a high tap water aluminium content and a known high incidence of dialysis encephalopathy, 29 patients undertaking regular home dialysis, without clinical evidence of encephalopathy, were studied with a battery of psychological tests that have proved useful in detecting early organic intellectual deterioration in other conditions. Full-scale intelligence quotient, as measured by the Wechsler Adult Intelligence Scale, did not differ significantly from that of the normal population, but the patients showed significant deficiencies in three tests of performance--namely, digit symbol, block design, and picture arrangement. The ability to acquire new information in relation to performance was impaired and the abnormality increased with time on dialysis. Such tests should be useful in early detection of dialysis dementia at a reversible stage.
To assess whether phosphate depletion is an aetiological factor in osteomalacic dialysis osteodystrophy we undertook a prospective trial of phosphate-enriched dialysis fluid, in association with oral 1alpha-hydroxycholecalciferol, for this condition. Thirty patients started the trial; of the 27 who completed more than 6 months' treatment, 14 had iliac crest bone biopsies at the beginning and end of the treatment period. Side effects included pruritus, stiffness, and increase in corneal and vascular calcification. Only one patient showed histological improvement of osteomalacia, and eight deteriorated; in seven the osteitis fibrosa worsened. Myopathy showed some improvement in four patients, but became worse in four. This treatment does not seem to have a place in the routine management of non-hypophosphataemic patients on dialysis.
Serum ionised calcium concentration [Ca2+] was measured with a calcium selective electrode in 65 normal people. A mean value of 1.06 mmol/l (+/- 0.04 S.D.) with an actual range of 0.97 to 1.13 mmol/l was obtained. Serum samples refrigerated at 4 degrees C for 24 h were satisfactory for analysis. Storage of whole blood samples for 6 h at room temperature before separation caused a very small error (+0.04 mmol/l). Mean results and ranges were similar in males and females and there was no significant correlation with age. No significant change in serum [Ca2+] was found following a normal meal. Serum [Ca2+] and total serum calcium showed a very slight correlation (r = 0.35). The method is reproducible and sensitive.
This paper explores in patients with dialysis osteodystrophy the relationship between clinical features and histological, radiological, and biochemical findings. Eighty-five patients treated by hemodialysis for more than 6 months were studied. The following conclusions were drawn: 1) Bone pain in patients on regular hemodialysis is usually a symptom of developing osteomalacia but not of hyperparathyroidism or osteoporosis. 2) Many patients with histological osteomalacia and radiological features of osteomalacia, such as fractures or Looser zones, have no symptoms. 3)In dialysis patients, biochemical and radiological abnormalities are not a reliable means of predicting the presence of osteomalacia, but a raised serum alkaline phosphatase is a good indicator of the presence of osteitis fibrosa. For early detection of osteomalacia, bone biopsy in necessary. 4)A number of our dialysis patients develop an unusual form of osteomalacia characterized by absent or minimal histological osteitis fibrosa, a normal serum alkaline phosphatase, and a high incidence of myopathy and fractures.
The inter-relationships between serum ferritin, hemoglobin, serum iron and total body iron stores were studied in 20 patients with chronic renal failure treated conservatively and in 20 patients on regular hemodialysis. There was no relationship between serum iron or transferrin and bone marrow iron deposits, but serum ferritin concentration was a good indicator of increased marrow iron stores. All patients with serum ferritin levels above 300 microgram/l had increased iron stores. Serum ferritin assay is a useful non-invasive technique for detecting iron overload in uremic and hemodialyzed patients.
The effects on neutrophil count and complement activity of five different haemodialysis membranes were studied. There was no correlation between the degree of neutropenia and intensity of complement activation. With cuprophan membrane both occurred simultaneously but to unrelated degrees; polyacronitrile induced mild, not significant neutropenia but marked activation of complement; polycarbonate membranes induced severe neutropenia without detectable complement activation. Where complement activation occurred it was via the alternative pathway. Haemodialysis induced neutropenia may have many causes and complement activation is probably not the major responsible factor.
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The pollution of the environment with Kepone (decachlorooctahydro-1,3,4-metheno-2H-cyclobuta[cd]pentalen-2-one) by an industrial manufacturer of the pesticide resulted in the contamination of several terrestrial media, including biological life, near the entry of the insecticide into the ecosystem. The substrata investigated and for which residue methodology was developed included river sediment, soil, water, shellfish, and finfish. Rigorous extraction techniques utilizing the Soxhlet apparatus and the Polytron tissue homogenizer were required for complete removal of Kepone from the samples. Finfish tissue was the most difficult to analyze. For this type of substratum, a preliminary cleanup by gel permeation chromatography was required to remove most of the lipid material followed by a micro Florisil column elution to eliminate polychlorinated biphenyls (PCB'S). Cleanup of shellfish and other environmental samples was accomplished with a micro Florisil column only. Electron capture gas chromatography was used to analyze the sample extracts. Recoveries of Kepone from fortified samples averaged 84% or greater.
A disabling osteomalacic syndrome seen only during regular hemodialysis is described. Its features include skeletal fractures, pain, suppression of pre-existing hyperparathyroidism, and failure to improve with any of the vitamin-D metabolites. Phosphate depletion may be an important etiological factor but this could not explain all cases. A trial with phosphate-enriched dialysate and 1alphaOHD3 resulted in sustained clinical improvement in 54% of the patients and healing of fractures in 33%. Other etiological factors independent of 1,25(OH)2D3 deficiency and phosphate depletion must be considered. Current, indirect evidence suggests that accumulation of water toxins including aluminium may be important.
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(1) The bone histology of 233 non-dialysed and 276 haemodialysed patients with chronic renal failure is reviewed. In non-dialysed patients osteitis fibrosa occurred in 83.7% and osteomalacia in 23.6% of patients. Osteomalacia was not found in the absence of osteitis fibrosa. In haemodialysed patients there was a more variable bone histology, sometimes resembling non-dialysed bone disease, but in general with a greater incidence of osteomalacia, especially with increasing time on dialysis. In some patients there was a predominance of osteomalacia accompanied by no or only mild osteitis fibrosa and the serum alkaline phosphatase was normal. (2) The results of treating twenty-six haemodialysed patients with 1alpha-hydroxyvitamin D3 (1alpha-OHD3) are described. Patients with osteomalacia and minimal or no osteitis fibrosa and a normal serum alkaline phosphatase (Group I) in general failed to respond and it is suggested that 1,25-dihydroxyvitamin D3 deficiency is not the sole factor responsible for the osteomalacia in these patients. In contrast, 1alpha-OHD3 therapy was effective in improving osteitis fibrosa and osteomalacia in some patients with moderate to severe degrees of osteitis fibrosa and osteomalacia (Group IIa) and in improving osteitis fibrosa where this occurred alone (Group IIb).