From the time haemodialysis became a maintenance treatment in the 1960s, it was clear that there were long term consequences for those with ESRD whose lives were being unnaturally prolonged by dialysis. Some were predictable given the incomplete control of uraemia provided by maintenance dialysis, for example renal anaemia and metabolic bone disease. These were soon being studied, their pathophysiology better understood, and new treatments (though not always highly effective) were soon being brought forward.
Other complications were less well predicted, notably cardiovascular disease, but this problem was soon apparent from the beginning of maintenance dialysis, and was very widespread.
But by the early 1970s, there were also some new clinical syndromes emerging which were not explained by known metabolic effects. These only affected a small minority of dialysis patients, apparently at random, and could be very severe:
These clinical states were severe and distressing, not least because their aetiology was at first a complete mystery. Stewart Cameron recalls: We never had the dialysis dementia at Guy’s. We ….. just watched in horror when we saw it happening in Newcastle and Sheffield and the other places.
Only by the late 1970s was it clear that these three syndromes were all due to aluminium intoxication, and the UK had played a prominent role in solving this mystery.
De-ionisation of the water used to generate dialysate was not routine practice in the early days in dialysis units, nor in the set ups provided for home haemodialysis. The very large volume of dialysate used for each treatment was generated by a proportionator mixing cleaned domestic water with concentrate, either in a central tank in the unit, or as designs improved soon in individual dialysis machines. Patients were directly exposed to large volumes of water with each treatment. Small molecule toxins in domestic water were not thought likely to put patients at additional risk, so additional water purification was not thought necessary when weighed against the extra costs of reverse osmosis units.
The appearance of these new clinical syndromes was geographically patchy, some centres saw no cases, in others it was rather common and very severe. In Sheffield a large home haemodialysis programme had been established and the nephrologist Margaret Platts (1924-2017) made the crucial observation that cases of fractures and dementia were geographically clustered. This led her to the hypothesis that there could be a contaminant in the water supply used by some patients not others. In a crucial 1977 paper (Platts MM et al. Br Med J. 1977 ;2(6088):657-60) she and her colleagues reported on 202 home dialysis patients of whom 11 developed dialysis encephalopathy, 21 suffered spontaneous fractures, and 36 who had undergone dialysis for over four years had neither of these complications. Water supplied to the homes of the patients with fractures or encephalopathy contained significantly more aluminium than that piped to the homes of patients without these complications. High bone aluminium concentrations were found in patients with encephalopathy. The paper concluded that ‘Patents who undergo dialysis in areas where water contains high aluminium concentrations should be supplied with deionisers’. Since variations in metal content in water supplies were not uncommon, and testing water supplies routinely for aluminium was unaffordable, it very soon became the norm in all dialysis centres in the UK and all home dialysis installations to incorporate reverse osmosis units. The impact was dramatic; once aluminium was removed from water (or the patient was successfully transplanted) the incidence of fractures diminished and there were no new cases of the feared dialysis encephalopathy. Those with established encephalopathy showed significant cognitive improvement, although some were left with residual paraplegia. Platts went on (Platts MM et al. BMJ 1984; 88(6422):969-72) to establish a ‘safe’ aluminium water level of < 1.0 mol aluminium per l (2.7 micrograms/100 ml). A low cost colorimetric aluminium analysis was soon being used by many water authorities. Aluminium analysis by the more expensive electrothermal atomic absorption was reserved for those patients receiving regular haemodialysis.
Platts also showed that the ingestion of aluminium hydroxide, very widely used as an oral phosphate binder at that time, did contribute significantly to the increased plasma aluminium concentration of these patients. Although modest in effect compared to exposure to contaminated dialysate, aluminium-based binders were very soon withdrawn from first line routine clinical use, and the use of aluminium cooking pots for dialysis patients was also eschewed.
The first proposal that dialysis encephalopathy was caused by aluminium came in a paper published in 1976 by Alfrey and his colleagues in the USA. But Margaret Platts 1977 paper was not only the first European report of the problem but provided convincing evidence of its relationship to aluminium exposure, and the benefit of aluminium removal.
The Newcastle unit, led by David Kerr, also had major problems with both dialysis encephalopathy and the fracturing osteomalacia associated with aluminium toxicity, which for a time earned the soubriquet ‘Newcastle bone disease’ (Ward MK et al. Lancet 1978: 1(8069):841-5) Their studies confirmed significantly higher brain aluminium concentrations in 7 subjects dying with dialysis encephalopathy, and that grey matter from the patients with dialysis encephalopathy contained about three times as much aluminium as white matter. Further brain aluminium levels remain elevated for up to four years after restoration of good renal function by transplantation (McDermott JR et al. Lancet 1978; 1(8070):901-4). They showed that it was duration of exposure to high aluminium water concentrations which was associated with overt clinical problems.
Any thought that this might be a highly localised problem in the regions which first reported it (South Yorkshire and Tyneside) was soon disproved by an epidemiological survey of 1293 patients in eighteen dialysis centres across the UK which showed a highly significant rank correlation of the incidence of both fracturing dialysis osteodystrophy and dialysis encephalopathy with the aluminium content of water used to prepare dialysate (Parkinson IS et al. Lancet 1979;1(8113):406-9).
There was now no doubt that aluminium was directly neurotoxic, impaired mineralisation, and also caused a microcytic hypochromic anaemia.
Happily the problem had been defined and its aetiology demonstrated, reverse osmosis in water purification systems for dialysis became the norm, and monitoring water supplies for aluminium was integrated into routine care.
Last Updated on February 8, 2024 by John Feehally