D.N.S. Kerr

FRACTURING DIALYSIS OSTEODYSTROPHY AND DIALYSIS ENCEPHALOPATHY: An Epidemiological Survey

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.

BRAIN-ALUMINIUM CONCENTRATION IN DIALYSIS ENCEPHALOPATHY

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.

VARIABLE RESPONSE TO LONG-TERM 1α-HYDROXYCHOLECALCIFEROL IN HÆMODIALYSIS OSTEODYSTROPHY

Ten uraemic patients on regular haemodialysis were treated with 1alpha-hydroxycholecalciferol (1alpha-H.C.C.) for 5 to 14 months. Five patients who had histological osteitis fibrosa with or without osteomalacia responded well, with resolution of musculoskeletal pain, return of raised serum-alkaline-phosphatase concentrations to normal, resolution of radiological subperiosteal erosions, and improvement in histological signs of osteitis fibrosa and osteomalacia. In these patients 1alpha-H.C.C. proved a safe and effective drug. Five other patients did not improve. Characteristically these patients started with moderately severe histological osteomalacia and minimal, if any, osteitis fibrosa. Proximal myopathy was a prominent symptom and serum-alkaline-phosphatase was normal in four of them. Treatment with 1alpha-H.C.C. resulted in early troublesome hypercalcaemia, and repeat bone histology 5--11 months later showed no improvement. It is suggested that in these patients lack of 1,25-dihydroxycholecalciferol may not have been wholly responsible for the observed osteomalacia, hence 1alpha-H.C.C. alone was ineffective. Phosphate depeltion may have been an important contributing factor.

HÆMODIALYSIS IN PARACETAMOL SELF-POISONING

Abstract Following paracetamol overdosage, haemodialysis removes the drug at a clearance-rate similar to that of creatinine. The plasma half-life of paracetamol is considerably reduced by haemodialysis, especially in patients with high initial plasma concentrations and hepatic damage. It is not known whether the quicker removal of the drug improves the prognosis, but the survival of one patient with a very high initial plasma concentration is a hopeful pointer. Pending a controlled evaluation of haemodialysis it would appear reasonable to use this form of treatment, where it can be applied swiftly and safely, for patients seen within 12 hours of ingesting at least 15 g. of paracetamol, provided the history can be corroborated by estimation of plasma-paracetamol levels.

ABSENCE OF A THERAPEUTIC EFFECT OF ZINC IN THE SEXUAL DYSFUNCTION OF HÆMODIALYSED PATIENTS

The effect of zinc therapy and placebo on sexual function and endocrine status was investigated in a double-blind study of 14 male patients with chronic renal failure on regular haemodialysis. Zinc chloride was added to the dialysate of 7 patients for 6 weeks, raising the serum zinc concentration by 17% and placebo was added to the dialysate of the other patients. At the start of the trial 9 patients said they had decreased sexual function. Records of penile erectile activity during sleep confirmed the organic nature of the sexual dysfunction. Plasma testosterone concentrations were low or in the low normal range, basal serum luteinising-hormone levels were raised, and the early luteinising-hormone response to luteinising-hormone-releasing hormone was exaggerated, suggesting primary testicular failure. Zinc administration had no significant effect on any aspect of sexual function assessed by questionnaire or nocturnal penile tumescence monitoring. Plasma testosterone and basal and stimulated gonadotrophin levels were also unaltered by zinc administration.

TREATMENT OF HEPATIC COMA BY EXTRACORPOREAL PIG-LIVER PERFUSION

Abstract Four patients in hepatic coma were treated by repeated extracorporeal pig-liver perfusions after failing to respond to standard medical treatment. One patient recovered consciousness completely after one perfusion, while the remainder showed lightening of coma or neurological improvement. In all patients perfusions were followed by a striking fall in blood-ammonia, bilirubin, and clotting-time together with a rise in prothrombin and fibrinogen. All patients had complications such as cessation of respiration, hypoglycaemia, anuria, and haemorrhage and they died 8, 5, 8, and 10 days from onset of coma. The average rate of survival from acute hepatic necrosis treated by conventional methods is about 10%; with exchange blood-transfusions it is 20%, and with extracorporeal liver perfusions about 18%. The use of extracorporeal liver is a safe and rational method of temporary hepatic support since, with good technique, such a liver can carry out the metabolic functions of a normal liver. Ultimate survival depends on the extent of the initial hepatic necrosis, on the rate of liver regeneration, and on the absence of certain lethal complications. Survival could be improved if standard treatment is combined with liver perfusion early and vigorously. While liver transplantation may be helpful for the treatment of encephalopathy due to cirrhosis, it is of doubtful value in cases of acute hepatic necrosis, particularly when caused by viral hepatitis.

FUNCTION OF THE HYPOTHALAMO‐HYPOPHYSIAL‐THYROID AXIS IN CHRONIC RENAL FAILURE

Hypothalamo‐hypophysial‐thyroid function has been studied in twenty‐five patients with chronic renal failure. Eight were receiving conservative treatment, nine peritoneal dialysis and eight haemodialysis. All were clinically euthyroid. Total thyroxine (T4) and triiodothyronine (T3) levels were reduced but free T4 levels were normal, while free T3 was reduced in patients with the most severe renal failure. It is suggested that the binding of thyroid hormones by the transport proteins is reduced and that peripheral conversion of T4 to T3 is impaired in renal failure. The thyrotrophin response to thyrotrophin‐releasing hormone (TRH) is reduced in renal failure but this reduction is probably independent of alterations in thyroid hormone metabolism. Growth hormone was released by TRH in seven of the patients studied, possibly as a result of protein malnutrition.

RENAL BONE DISEASE ‐ WHAT IS IT AND WHY DOES IT HAPPEN?

There are three main components of renal osteodystrophy; osteitis fibrosa, osteomalacin, and changes in bone mass. The incidence of these factors changes during the progression from early renal failure to regular dialysis and renal transplant. Many of the factors influencing the development of these features and their changing patterns are unknown. With the aid of our experience in Newcastle we will illustrate the clinical spectrum of renal osteodystrophy, and introduce some of the aetiological, clinical and therapeutic problems which will be considered in this symposium. Osteitis jibrosa (OF) is common in patients with chronic renal failure who are not on dialysis. Before vitamin D derivatives were avdable OF was present in bone biopsies of 80% of our patients at the time of starting regular dialysis. In patients on regular haemodialysis the course of OF varied with time, some cases healing, some deteriorating, others fluctuating or remaining unchanged as months went by. Overall there was a small fall in the incidence and severity of OF in the first 18 months on dialysis, but in patients surviving over 4 years on dialysis there was an increase in both severity and frequency of the lesion. Following renal transplantation, OF heals slowly radiologically in our patients, and elevated serum levels of ionized calcium and parathyroid hormone may persist for many months, hyperparathyroidism recurring rapidly with graft fdure . OF only gives rise to symptoms in severely affected patients after many months, (Siddiqui et al., 1971), althouth we suspect the prolonged hypercalcaemia after renal transplant may play a role in some cases of graft fadure. The course of hyperparathyroidism in chronic renal f d u r e and dialysis has been modified by administering aluminium hydroxide and calcium carbonate (Hill et uf., 1975) (although on this regimen there was an increase in osteomalacia), by giving large doses of vitamin D or dihydrotachysterol, and by manipulation of dialysate calcium levels. Despite these measures, many patients are unresponsive, and a significant number develop severe, apparently autonomous, hyperparathyroidism, with hypercalcaemia, bone lesions, and widespread soft tissue, corneal, and vascular calcification. The use of 1-hydroxylated vitamin D derivatives has been a more successful therapy for OF as will be shown by Dr Ellis and others later in t h i s symposium.

Glycerol Instead of Dextrose As an Osmotic Agent in CAPD

Glycerol replaced dextrose as the osmotic agent in dialysis fluid for six patients undergoing CAPD. This resulted in lower plasma glucose concentrations and insulin levels. No toxicity was detected from glycerol absorption, even in one patient so exposed for 6 months. On a molar basis, however, glycerol induced less ultrafiltration than dextrose did. Because of the lower dialysate volume, clearances were less with glycerol than with dextrose.

Sexual Dysfunction in Patients Treated by CAPD

A comparison of sexual function in 27 male CAPD patients with that of 73 male hemodialysis patients revealed impotence in more than half of each group and testicular atrophy in the vast majority. Gynecomastia was infrequent. Plasma testosterone levels were higher in the CAPD population but differences in prolactin, FSH, TH and PTH were minor. The similarities in sexual function of hemodialysis and CAPD patients do not support middle molecule toxicity as a major pathogenetic factor in uremic sexual dysfunction.