Renal bone disease

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Renal bone disease

New technologies – unanticipated consequences

Renal bone disease emerged in the 1970s as a major issue causing significant disability.  Before the establishment of haemodialysis services in the late 1960s bone disease in adults with end-stage renal failure was something of a rarity, though the entity of ‘renal rickets’ in children and adolescents was recognised.  Our understanding of its pathogenesis and natural history was limited and therapeutic options even more so.    Britain’s leading expert from the 1950’s was Bill Stanbury from Manchester who wrote presciently “it may consist of several distinct components of probably differing pathogenesis, which are active in varying degree in different patients; these components may occur alone or variously admixed; and, in the course of time, one pattern of bone disease may become transformed into another”.

Calcitriol production by the kidney

A major breakthrough was the discovery by David Fraser and Egon Kodicek in Cambridge in 1971 that the hormonally-active form of vitamin D (calcitriol) was synthesised in the kidney.  This gave a tremendous impetus to research, and very soon synthetic calcitriol and its analogue, alfacalcidol, were made available.  The latter was the first to become available to British researchers and clinicians (1973).

Bone biopsies and the effect of alfacalcidol

The Oxford group, led by John Kanis, were amongst the leaders in this research.  They were interested both in the natural history of renal bone disease and its responses to treatment, and relied heavily on sequential histological assessment of bone biopsies from dialysis patients, usually taken two-yearly.  The author  himself performed all the bone biopsies in the Oxford studies from 1977-1979; reflecting prevailing attitudes to research governance at that time, he recalls that the bone biopsies were  regarded as part of ‘routine care’, and that patient compliance was very high.

These studies confirmed Stanbury’s suggestions – renal bone disease was heterogeneous and could change over time.  It tended to progress from normal, through a mixed picture of hyperparathyroidism with osteomalacia, then to severe hyperparathyroidism (osteitis fibrosa).  

The hyperparathyroidism / osteomalacia group responded best to alfacalcidol with resolution of symptoms, reduction in ALP levels and radiographic healing of bone disease (though histological resolution was less complete). 

Alfacalcidol treatment in the osteitis fibrosa group turned out to be less successful, being limited by treatment-induced hypercalcaemia.  However, excellent resolution of osteitis fibrosa occurred after parathyroidectomy, but a mysterious disorder developed in some people who had undergone total parathyroidectomy: a fracturing bone disease with myopathy and low ALP levels, due to a form of osteomalacia that was completely unresponsive to vitamin D treatment.

Aluminium bone disease

Victor Parsons and colleagues had demonstrated in 1971 that aluminium could accumulate in bone, and that concentrations seemed to differ between patients from different renal units, but the clinical importance of this observation was not appreciated at the time.  

In 1972, researchers in Denver first described dialysis encephalopathy, a horrible condition affecting people who had been on dialysis many years, characterised by speech disturbance, myoclonic jerks and dementia.  This syndrome was soon recognised elsewhere, but was markedly more common in some renal units than others.

In Sheffield a large home haemodialysis programme had been established and the nephrologist Margaret Platts made the crucial observation that cases of fractures and encephalopathy were geographically clustered together, and she hypothesised that in some localities a contaminant in the water supply could be responsible.

Newcastle-upon-Tyne was particularly affected, and researchers in David Kerr’s unit there showed in 1978 that aluminium accumulation was the cause of both the vitamin D resistant osteomalacia and dialysis encephalopathy.  They were further able to show that it was the aluminium content of the water used to make up dialysate that was responsible, and that the marked regional variation in prevalence was due to differences in the amount of aluminium sulphate added to local water supplies as a flocculating agent.    Read more about the British contribution to the understanding of aluminium intoxication in dialysis patients.

Post-transplant osteoporosis and steroids

Renal transplantation was taking off by the mid-1970s and at this time immunosuppression was reliant on high dose steroids and azathioprine.  Another unanticipated bone complication was the high rate of osteonecrosis (avascular necrosis) of the hips, often disabling people with well-functioning grafts. Peter Morris and his colleagues in Oxford demonstrated that graft function was not compromised by using lower doses of steroids – and found a bonus side effect of a markedly reduced rate of osteonecrosis.

Impact on modern practice

In modern nephrological practice many things are taken for granted – the early use of calcitriol or alfacalcidol, the intensive use of phosphate-binding agents, monitoring of parathyroid hormone levels (assays for which were inaccurate in renal failure before the 1990s), monitoring of serum aluminium levels, reverse osmosis treatment of dialysate, and parathyroidectomy with implantation of some resected tissue into muscle or subcutaneously.  All these practices developed from lessons, sometimes painfully learned, in those early years. 

In that era, older people were not admitted to dialysis programmes, so in recent times the nature of bone disease has shifted again, with current research more focused on bone loss, osteoporosis and fracture and the relationships of disturbed mineral metabolism to vascular calcification. However the other reason for that shift has been the great reduction in clinical osteodystrophy – presumably due to treatment with alfacalcidol and calcitriol.

Authorship

Tim Cundy

Last Updated on November 16, 2024 by neilturn