Aluminium intoxication in renal disease.

Aluminium intoxication in renal failure occurred over weeks or months when dialysis fluid or parenteral solutions were heavily contaminated and over many years when the main source was oral administration of aluminium-containing phosphate binders. Encephalopathy was common during subacute intoxication but in slow aluminium poisoning the main brunt was borne by the bones. However, in both tempos of intoxication several organs or systems were involved. Encephalopathy was usually accompanied by bone disease, bone disease by parathyroid suppression and both by anaemia. The heart and the lymphocytes are probably damaged by aluminium overload. Among the many questions left unanswered 15 years after the incrimination of aluminium as the cause of this multi-system illness are: (1) does low level aluminium overload in renal failure cause gradual deterioration in cerebral function? And, if so, (2) does it resemble Alzheimer's disease or a slow-onset version of dialysis encephalopathy? The evidence we review suggests that the answer to (1) is 'yes' and to (2) 'probably the latter'.

Parathyroidectomy in chronic renal failure: a nine-year follow-up study.

Seventy-three patients with chronic renal failure who underwent parathyroidectomy between March 1978 and April 1987 were reviewed. Thirty-four patients had undergone sub-total parathyroidectomy, and 39 patients had undergone total parathyroidectomy with parathyroid autograft into the forearm. Eight patients showed persistent hyperparathyroidism requiring a second surgical procedure. In all other patients there was highly statistical improvement in parathyroid hormone, total calcium, ionized calcium, alkaline phosphatase and a significant reduction in calcium x phosphate product. Histological evidence of osteitis fibrosa was present in 21 of 22 patients before surgery. Postoperatively, four showed complete resolution and improvement. Three patients developed histological evidence of osteomalacia during the study period. Only four of the 39 patients who underwent total parathyroidectomy with autograft had true recurrent hyperparathyroidism and only two of the 34 patients who underwent sub-total parathyroidectomy had recurrent disease, indicating that there is little to choose between the two techniques in the control of secondary hyperparathyroidism and its subsequent recurrence. In one patient with recurrence of hyperparathyroidism from a forearm parathyroid graft the histological picture was different from that of normal hyperplastic parathyroid tissue. Although it is probable that abnormal parathyroid tissue had been implanted there was no evidence of invasive growth into the forearm muscle. The most striking feature of long term follow-up was the difference in calcium x phosphate product in patients in whom vascular calcification increased compared to those patients with no change or regression of calcification. Mean calcium phosphate product in those patients with progressive vascular calcification was 4.93 for small and medium size vessels and 5.38 for large vessels compared to 4.10 for small and medium vessels and 4.09 for large vessels. In the former case the serum phosphate was 2.00 and 2.17 as compared to 1.75 or 1.73, suggesting that the aim in patients with end stage renal failure maintained by dialysis should be to control the serum phosphate concentration to 1.8 mmol or less and the calcium x phosphate product to less than 4.2.

Ultrastructure of parathyroid autografts in chronic renal failure including the occurrence of concentric membranous bodies and intermediate filaments.

The ultrastructure of long-term parathyroid autografts and their donor glands has been studied in nine patients with chronic renal failure. Autografts showed ultrastructural features of functional activity. Unusual findings included the presence of 'spironolactone-like' concentric membranous bodies derived from the endoplasmic reticulum in one hyperplastic autograft and prominent intracellular intermediate filaments (tonofilaments) in the donor parathyroid gland and recurrent autograft growths in another patient.

Critical analysis of the use of skeletal surveys in patients with chronic renal failure.

Skeletal radiology and bone histopathology were compared in 82 patients with renal failure. The performance of radiology in detecting lesions was assessed using interobserver studies which showed disappointing levels of agreement probably reflecting the subjective nature of the radiological signs. Radiology was very insensitive in detecting and grading hyperparathyroidism even when histology and serum biochemistry were floridly abnormal. The most useful radiographs for monitoring subperiosteal erosions and vascular and soft tissue calcification are identified.

Demonstration of aluminium in iliac bone: correlation between aluminon and solochrome azurine staining techniques with data on flameless absorption spectrophotometry.

The presence of excess aluminium was investigated in 204 samples of iliac bone from 197 patients with chronic renal failure by using the aluminon and solochrome azurine staining techniques. The results were compared with values obtained by atomic absorption spectrophotometry (AAS). Overall, the staining reactions correlated with the AAS data, but the solochrome azurine stain was positive more often than was the aluminon stain (in 90.6% and 62.3%, respectively, of bone samples with greater than the control group mean +3SD (that is, in the range 17.8 to 113.4 micrograms aluminium/g Solochrome azurine staining was consistently positive in all cases, with greater than 23.1 micrograms aluminium/g bone but the corresponding aluminon stain was occasionally inexplicably negative in this range. In some samples solochrome azurine was positive in parts of old unresorbed cement lines when the aluminon stain was negative and the bone aluminium concentration was within the normal range or slightly increased. The stains, particularly solochrome azurine, have the advantage over AAS in that they indicate the location as well as the presence of excess bone aluminium.

Fate of long-term parathyroid autografts in patients with chronic renal failure treated by parathyroidectomy: a histopathological study of autografts, parathyroid glands and bone.

The aims of the study were to (1) determine the histopathology of parathyroid autografts in patients with renal failure treated by parathyroidectomy, (2) relate this to any evidence of hyperfunction, such as histological osteitis fibrosa and (3) determine whether there were any features in the donor parathyroid glands which correlated with autograft behaviour. Fourteen patients were studied; 106 implanted parathyroid fragments were identified in nine at necropsy and in the remaining five patients multiple fragments were obtained at the time of autograft surgical reduction. Of the patients studied at necropsy, in two the autografts were small and hypofunctional and in one of these the implants appeared partially involuted. In neither was there osteitis fibrosa. In the others there were varying degrees of hyperplasia and osteitis fibrosa. Four of the surgically excised autografts were markedly hyperplastic but there was no unequivocal evidence of malignancy. In one case, requiring repeated reduction of rapidly growing autograft tissue, there were frequent mitoses in the donor parathyroid gland and in the autograft. The presence of atypical cellular features and frequent mitoses in intraoperative frozen sections of a parathyroid gland militate against its use for implantation.

Polycystic disease of the parotid glands: case report of a rare entity and review of the literature.

We report a case of polycystic disease of the parotid glands. This is a rare disorder and we know of only two previous documented cases in the literature. The disease presents with painless enlargement of one or both parotid glands and is not associated with any clinical abnormality of salivation or with any apparent anomaly of the other salivary glands. Histologically, the overall glandular architecture is preserved but the lobules are all markedly distended by epithelial-lined cysts, which appear to be derived from the intercalated ducts. Characteristic congophilic laminated spheroliths are present within the cystic spaces. The condition must be differentiated from cystic neoplasms, particularly papillary cystic adenocarcinoma, and from various non-neoplastic disorders including sialectasia, retention cysts and lymphoepithelial cysts.

Parathyroidectomy in chronic renal failure.

In order to establish whether parathyroidectomy altered the natural history of ectopic calcification in patients with renal failure we undertook a detailed analysis of 62 patients with hyperparathyroidism secondary to chronic renal failure who were submitted to parathyroidectomy. Biochemical data (61 patients) and radiological skeletal surveys (42 patients) were studied before and after parathyroidectomy. Transiliac bone biopsies were obtained at (or some time in the previous six months before) parathyroidectomy in 30 and in 36 patients after surgery. Paired bone biopsies were available from 17 of these patients. In the majority of patients secondary hyperparathyroidism was controlled after parathyroidectomy although in seven patients (11 per cent), who underwent subtotal parathyroidectomy, it relapsed after initial improvement. Non-visceral soft tissue calcification disappeared or decreased in 60 per cent of the patients after parathyroidectomy. However, despite marked improvement in subperiosteal erosions and histological osteitis fibrosa, with significant reductions in iPTH and Ca X P product after parathyroidectomy, small peripheral arterial calcification developed or progressed in 56 per cent of the patients. Histological osteomalacia after parathyroidectomy developed after operation in two patients. Both had positive aluminium stains for excess aluminium in their bone. Numbers of osteoclasts and the amount of marrow fibrosis declined in parallel following parathyroidectomy, but woven bone persisted for months or years.

Renal osteodystrophy and metastatic calcification in long-term continuous ambulatory peritoneal dialysis.

The biochemical data and drug histories related to bone disease were extracted from the case records of 47 patients who had been treated by continuous ambulatory peritoneal dialysis (CAPD) for more than two years. These data were reviewed in conjunction with the skeletal surveys done over the same period in all patients, with particular reference to secondary hyperparathyroidism, osteomalacia and non-visceral metastatic calcification. Paired bone biopsies were available in 20 of these patients and the histology was quantitated. In the majority of our patients secondary hyperparathyroidism was controlled or improved on CAPD. Osteomalacia also improved in two of the three patients in whom it was initially present and did not develop in any patient whilst on CAPD. We did, however, note a high incidence of non-visceral metastatic calcification. Small vessel calcification developed in 19.6 per cent of patients, large vessel calcification developed in 23.9 per cent and soft tissue calcification developed in 21.7 per cent of patients. We conclude that CAPD, as a form of treatment for end-stage renal disease, satisfactorily controls the osteodystrophy associated with renal failure in the majority of patients. The significance of the high incidence of non-visceral metastatic calcification remains to be established.

Ectopic calcification. The role of parathyroid hormone.

In 42 uraemic patients radiological skeletal survey, biochemistry and bone histology were compared before and at 6-12 months (42 patients), 12-24 months (26 patients) or 24-48 months (12 patients) after parathyroidectomy. The presence of small vessel or non-visceral soft tissue calcification was not related to the age, sex, duration of end-stage renal failure treatment, total serum calcium, magnesium, phosphate, Ca x P product, alkaline phosphatase, ionised calcium, serum aluminium, iPTH, severity of radiological and histological osteitis fibrosa or parathyroid gland weight. Twenty-three patients (55%) had small vessel and 20 (48%) soft tissue calcification before parathyroidectomy. Despite a marked improvement in subperiosteal erosions (37 healed, 5 improved) and healing of osteitis fibrosa histologically, seven patients developed new and six developed increased peripheral arterial calcification while in 10 patients non-visceral soft tissue calcification disappeared and in two decreased. Successful parathyroidectomy improves non-visceral calcification but not arterial calcification despite reduction in Ca x P product and iPTH.

Osteomalacia due to ileal replacement of ureters: report of 2 cases.

We report 2 cases of ileal replacement of the ureters: 1 bilateral and 1 unilateral with a single kidney. Hyperchloremic acidosis developed in both patients and osteomalacia was proved by iliac bone biopsy. Patient 1 had symptomatic bone disease and control of acidosis with sodium bicarbonate was difficult because of associated hypertension. The level of alkaline phosphatase varied inversely with the level of serum bicarbonate. Pharmacological doses of 1-alpha hydroxycholecalciferol were ineffective and osteomalacia persisted in a second biopsy. Patient 2, who was asymptomatic, suffered acidosis and increased serum alkaline phosphatase levels immediately postoperatively and osteomalacia was confirmed histologically at 6 months.

Bone disease in long-term hemodialysis patients with low dialysate aluminium.

The dialysis unit in Sunderland uses softener water treatment with low Al concentration (dialysate mean Al 22 micrograms/L) but employs continuous oral Al (OH)3 to control serum phosphate. Thirty-one patients, 22 males and 9 females, with a mean age of 45 years, maintained on hemodialysis for a mean of 48 months were studied. Patients had higher Al concentrations than normal controls (p less than 0.001) and the postdialysis serum Al levels were also significantly higher than the predialysis levels. Twenty-four of 31 patients had evidence of hyperparathyroidism on radiology but only 4 of 31 had fractures. From a histopathological point of view, the patients were found to have no lesions (4 patients), osteitis fibrosa alone (17 patients), and osteitis fibrosa combined with osteomalacia (5 patients). The effect of 1-alpha(OH)D3 treatment was checked by repeated bone biopsies. One case of the last group showed no improvement of osteitis fibrosa, while osteomalacia progressed to severe. We conclude that both antacids and dialysate contribute to the serum and tissue Al accumulation in Sunderland Renal Unit, where over a period of ten years only one patient developed Al-related osteomalacia.

Osteomalacia in patients with chronic renal failure before dialysis or transplantation.

The case records of 327 patients who underwent bone biopsy in late or terminal renal failure, before any form of dialysis or transplantation, were examined for clues to the aetiology of renal osteomalacia and its manifestations. Fifty four per cent of the biopsies showed pure osteitis fibrosa, 34 per cent osteomalacia with osteitis fibrosa and 12 per cent showed neither abnormality. Osteomalacia was strongly associated with chronic pyelonephritis and obstructive uropathy as primary renal disease. In two matched groups of 100 each, and within the major primary diseases, it was associated with acidosis, hypocalcaemia and normophosphataemia (as opposed to hyperphosphataemia). There was no association with known length or uraemia and only a weak and inconsistent relationship with severity of uraemia. In the few patients studied, there was no relationship between osteomalacia and serum 25-hydroxycholecalciferol level. In contrast to the state of patients treated by haemodialysis, osteomalacia in this undialysed group was manifested by a higher level of serum alkaline phosphatase than pure osteitis fibrosa, serum iPTH did not differ between the groups, there was no predominance of symptoms in one group, other than proximal myopathy which had a weak association with osteomalacia, and Looser zones were more common than complete fractures. Our study shows that osteomalacia has different manifestations, and probably different causes, before and after the start of haemodialysis. These two stages of renal failure should be clearly distinguished in reports of renal bone disease.

Osteomalacia in chronic renal failure before dialysis.

Bone biopsies taken from 327 patients before the start of dialysis have been correlated with clinical and biochemical findings to test various theories about the aetiology of osteomalacia. Two groups of patients, 100 with osteomalacia and 100 with pure osteitis fibrosa, have been compared in detail. Osteomalacia is associated with chronic pyelonephritis or obstruction as primary renal disease, and with acidosis, hypocalcaemia and normophosphataemia (as opposed to hyperphosphataemia). We have found no association between osteomalacia and known duration or severity of uraemia and in a small series of observations we have not confirmed previous reports of a close association between osteomalacia and depressed plasma 25(OH) cholecalciferol values.

Pseudarthrosis of the radius associated with neurofibromatosis. A case report.

A seven-year-old-boy with neurofibromatosis developed pseudarthrosis of the radius. After treatment by external electrical stimulation of the forearm failed, the pseudarthrosis was excised and the proximal and distal ends of the radius were osteotomized. The bone segments were reversed to correct the deformity and to place bone adjacent to the pseudarthrosis in contact with normal bone. This operation has not been described previously for this condition and, as in all previous reports, failed to produce union. Surprisingly, the excised pseudarthrosis showed no histologic evidence of neurofibroma or impaired osteoblastic function. The surrounding soft tissues may play an important role in the establishment and maintenance of the condition.