Aluminium Toxicity

By the 1970s, maintenance haemodialysis was a well-established treatment for irreversible kidney failure. And it was clear that there were long-term consequences for those with kidney failure whose lives were being unnaturally prolonged by dialysis, associated with the incomplete control of uraemia: for example, anaemia and metabolic bone disease.  

A devastating new syndrome

But by the early 1970s, there were also 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:

• Despite treatment to control secondary hyperparathyroidism and vitamin D deficiency, some patients were developing a severe fracturing osteomalacia
• Others had rapidly progressive loss of cognitive function, leading to dementia with myoclonus, a particularly prominent clinical feature.
• Others had an unusually severe hypochromic microcytic anaemia.

These clinical states were severe and distressing, not least because their aetiology was at first a complete mystery. Stewart Cameron recalled: "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.

Sheffield

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 but not others.

Could water be the explanation?

De-ionisation of the water used to generate dialysate was not routine practice in the early days in dialysis units, nor in the setups 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 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 to be a major issue, so there was no additional water purification.

Aluminium

In a crucial 1977 paper, Platts and her colleagues ( Br Med J. 1977 2:657-60 ) reported on 202 home dialysis patients of whom 11 developed dialysis encephalopathy, 21 suffered spontaneous fractures, but 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 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 also provided convincing evidence of its relationship to aluminium exposure, and the benefit of aluminium removal.

It turned out that some water authorities chose to dump large amounts of aluminium salts into the domestic supply to aid the removal of particulates, while others did not. Thus, large variations in aluminium content in water supplies were common, and 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.

Other sources of aluminium

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 serum aluminium concentrations in these patients. Although modest in effect compared to exposure to contaminated dialysate, aluminium-based binders were soon withdrawn from first-line routine clinical use, and the use of aluminium cooking pots for dialysis patients was also eschewed.

Newcastle and beyond

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).

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 eighteen dialysis centres across the UK which showed a highly significant correlation of the incidence of both fracturing dialysis osteodystrophy and dialysis encephalopathy with the aluminium content of the 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.