TOMORROW'S ARTIFICIAL KIDNEY?

446 and morbidity. At necropsy the brain shows no evidence of inflammation or demyelination but is uniformly swollen and there may be neuronal loss. There is periportal fatty infiltration, and the hepatocytes have swollen pleomorphic mitochondria and small droplet triglyceride accumulation.53 The renal tubules and heart are likewise infiltrated with fat. Although renal involvement is usually mild, acute renal failure may occur. 54 Reye’s syndrome is probably commoner than is realised, and a critical re-examination of children with " status epilepticus ", " toxic encephalopathy or acute brain swelling ", and " ence.phalitis with normal cerebrospinal fluid " is likely to reveal more cases. Research into the pathogenesis of this condition has been mainly epidemiological and chemical. A similar condition with a high mortality is very common in Thailand 55 ; but only 70% of these patients had raised transaminase concentration, and hyponatraemia and hyperkalæmia were common. The evidence linking this encephalopathy to aflatoxin produced by the fungus Aspergillus flavus in food is considerable: the toxin is present in higher concentrations in food in the more susceptible areas and at the time of the year when the incidence of the disease is highest; a very similar disease is produced by giving the toxin to young monkeys; and higher concentrations are found in tissues of children dying of encephalopathy and fatty degeneration of viscera than from other A viral aetiology has been suggested, with causes. influenza B and varicella as the likely agents.56-60 The evidence for influenza B virus as a cause is strengthened particularly by a detailed epidemiological and virological study from Cincinnati of an epidemic of 24 typical cases in the first three months of this year.61 This coincided with an epidemic of influenza B intermediate strain infection. Although evidence of infection by several viruses was found, influenza B predominated. The virus was cultured from the nasopharynx in 9, in a further 3 there was a fourfold rise in hsemagglutination-inhibition antibody, and in 5 other patients a close contact had similar evidence of infection with this strain of virus. Tests of cellular

high mortality

,

immunity using phytohaemagglutinin and specific viral antigens were normal in 6 patients. All patients had been given aspirin; but apart from this and their youth, no other common factor was evident. The high concentrations of ammonia in blood and cerebrospinal fluid in the acute phase 62,63 could 53. Partin, J. C., Schubert, W. K., Partin, J. S. New Engl. J. Med. 1971,

285, 339. 54. Nicholls, S., Gill,D. S., Chantler, C., Barratt, T. M. Unpublished. 55. Olson, L. C., Bourgeous, C. H., Cotton, R. B., Harikul, S., Grossman, R. A., Smith, T. J. Pediatrics, 1971, 47, 707. 56. Huttenlocher, P. R., Schwartz, A. D., Klatskin, G. ibid. 1969, 43, 443. 57. Glick, T. H., Likosky, W. H., Levitt, L. P., Melling, H., Reynolds, D. W. ibid. 1970, 46, 371. 58. Reynolds, D. W., Riley, H. D., La Font, D. S., Vorse, H., Stout, C., Le Roy, R. J. Pediat. 1972, 80, 429. 59. Hopkins, I. J., Connelly, J. F., Dawson, A. G., Hird, F. J. R., Maddison, T. G. Archs Dis. Childh. 1969, 44, 143. 60. Glick, T. H., Ditchek, N. T., Salitsky, S., Freimath, E. J. Am. J. Dis. Child. 1970, 119, 68. 61. Linnemann, C. C., Shea, L., Kauffman, C. A., Schiff, G. M., Partin, J. C., Schubert, W. K. Lancet, July 27, 1974, p. 179. 62. Kang, E. S., Gerald, P. S. N. Engl. J. Med. 1972, 286, 216. 63. Hilty, M. D., Romshe, C. A., Delamater, P. V. J. Pediat. 1974, 84, 362.

for the rapid progression of the encephalopathy, and some clinicians have tried liver-failure regimens, exchange transfusion, and peritoneal dialysis in treatment. Lately, evidence has been accumulating of a disturbance of urea-cycle pathways, producing a chemical picture similar to the genetically determined deficiency diseases of urea-cycle enzymes which usually present acutely in the newborn period." The main findings are high concentrations of glutamate, alanine, and lysine, low concentrations of arginine, and absence or very low concentrations of citrulline, suggesting a deficiency of the mitochondrial enzyme ornithine transcarbamylase.63,65 The lack of citrulline, as well as excluding one pathway for ammonia detoxication, prevents further detoxication of ammonia to urea. Because of this, a group from the Massachusetts General Hospital 65 gave L-citrulline to 3 children with Reye’s syndrome who were in decerebrate coma-the treatment suggested for the congenital enzyme deficiency. 57,66 The ammonia levels fell rapidly and the patients survived, and the Boston workers conclude that this method of treatment deserves further study. On p. 438 this week Dr Thaler and his colleagues record the case of a girl who developed 9 2-year-oldLiver the syndrome after varicella. biopsy showed typical histology, and ornithine-transcarbamylase activity in the liver was 20-7% of normal, with a low affinity of the enzyme for ornithine and substrate inhibition by carbamylphosphate and ornithine. The hyperammonsemia would thus be explained more by the anorexia and vomiting, with reduction of ornithine intake, than by high protein intake. Their suggestion that this alteration in the kinetic properties of the enzyme is genetically determined is not as yet supported by any family studies. Their patient recovered without specific treatment, but they favour trial of ornithine and arginine in high doses. The indications, therefore, are that there may be several causes of Reye’s syndrome, including viruses and ingested toxins, and that a disturbance of urea-cycle enzymes causing hyperammonæmia is probably an important factor in the neurological manifestations. The rapid diagnosis and treatment of hyperammonaemia has now become an important part of the management of coma of uncertain

account

cause

in childhood.

TOMORROW’S ARTIFICIAL KIDNEY? WITH the development in 1960 of a cannulation technique 67,68which allowed access to a patient’s circulation for repeated haemodialyses came the first report of successful prolongation of useful life, in two patients who were dying in chronic renal failure."

Since then, maintenance hæmodialysis has become an established form of treatment. Despite considerable E., Efron, M. L. in The Metabolic Basis of Inherited (edited by J. B. Stanbury, J. B. Wyngaarden, and D. S. Fredrickson); p. 37. New York, 1972. DeLong, G. R., Glick, T. H., Shannon, D. C. New Engl. J. Med. 1974, 290, 488. Kang, E. S., Snodgrass, P. T., Gerald, P. S. J. Pediat. 1973, 82, 642. Quinton, W., Dillard, D., Scribner, B. H. Trans. Am. Soc. arnf. intern. Org. 1960, 6, 104. Scribner, B. H., Caner, J. E. Z., Buri, R., Quinton, W. ibid. p. 88. Scribner, B. H., Buri, R., Caner, J. E. Z., Hegstrom, R., Burnell, J. M. ibid. p 114.

64. Shih, V. Disease 65.

66. 67.

68. 69.

447

advances, the principle in routine haemodialysis

equipment remains that of removal by diffusion natural across a semipermeable membrane of those whose accumulation substances " and unnatural leads to the syndrome termed uraemia.’ ° Technological development is here so near perfection that further advances will probably demand a new approachespecially if miniaturisation, cheapness, and simplicity The work of Prof. T. M. S. Chang, are sought. based on the principle of adsorption, seems to have considerable promise. He has designed a microcapsule artificial kidney " which contains albumincoated cellulose-nitrate-microencapsulated activated charcoal. The patient’s blood flows through a bed of 300 g. of microcapsules contained in a cylindrical chamber 8 cm. high and 10 cm. in diameter, and then returns through an air and clot trap to the systemic circulation. For patients with external arteriovenous shunts no blood pump or other equipment is needed. Professor Chang 71 reports that 15 patients with chronic renal failure have been treated successfully with the microcapsule artificial kidney, 3 of them for more than six months. Although, without a membrane, removal of water is still a problem, it seems that his system may be the basis of tomorrow’s artificial kidney for chronic-renal-failure patients. "

"

PENICILLINS AND NEPHROPATHY

nephropathy caused by penicillins are but we cannot be entirely confident that the condition is so rare. To be certain that a drug REPORTS of

penicillins, renal involvement apparently is not. Thus, when nephropathy is reported in 16% of 80 children treated with methicillin for staphylococcal pneumonia or osteomyelitis, 7additional factors must be suspected-a suspicion strengthened by the fact that similar treatment of severe staphylococcal infections in another hospital produced rash, fever, and eosinophilia in some children but no urinary abnormalities.81 The combination of hxmaturia and patchy interstitial inflammatory exudate might have suggested multiple small emboli, but such findings were absent from all but 2 of 54 children whose staphylococcal infections were treated with other antibiotics. Rash, fever, and eosinophilia did not complicate the treatment of the 54 children not given penicillins; the 2 with microscopic hæmaturia were being treated with kanamycin. The nephropathy caused by penicillins may be sufficiently intense to cause renal failure,77 and renal function may remain permanently impaired. 19 Although hypersensitivity appears to be the culprit, the possibility cannot be entirely discounted that very large doses of penicillins given for a long period may prove to be directly nephrotoxic. No therapeutic friend is entirely beyond the suspicion of causing occasional harm, and the most valued penicillins may occasionally have one or more renal stings in their tail. We must also remember that penicillins and cephalosporins share a chemically active &bgr;-lactam ring and that cross-allergenicity is sometimes found between them,72although fortunately it is uncommon. 82

not common,

used in the treatment of severe microbial disease is or is not nephrotoxic is difficult indeed. Severe infections with streptococci, pneumococci, and probably with staphylococci too may each provoke glomerulonephritis ; small emboli (whether infected or not) may cause patchy interstitial nephritis; and any severe illness may be complicated by acute tubular necrosis. Notwithstanding this complicated backtwo ground, groups of paediatricians have reaffirmed that the nephropathy caused by penicillins-specifically methicillin 72 and ampicillin 73 -cannot be ignored. There is no reason to suppose, however, that these two penicillins are any more or less nephrotoxic than any others. The nephropathy, which takes the form of acute interstitial nephritis, is regarded as an expression of hypersensitivity,73-80but, whereas rashes, fever, and eosinophilia are commonplace during treatment with 70.

Abel, J. J., Rowntree, L. G., Turner, B. B. J. Pharmac. exp. Ther. 1914, 5, 275. 71. Chang, T. M. S. in Renal Dialysis. Edited by D. WHELPTON. London: Sector Publishing. 1974. Pp. 152. £4.20. 72. Sanjad, S. A., Haddad, G. G., Nassar, V. H. J. Pediat. 1974, 84, 873. 73. Ruley, E. J., Lisi, L. M. ibid. p. 878. 74. London, D. R. ibid. 1967, 70, 285. 75. Simenhoff, M. L., Guild, W. R., Dammin, G. J. Am. J. Med. 1968, 44, 618. 76. Brauninger, G. E., Remington, J. S. J. Am. med. Ass. 1968, 203, 125. 77. Baldwin, D. S., Levine, B. B., McCluskey, R. T., Gallo, G. R. New Engl. J. Med. 1968, 279, 1245. 78. Gilbert, D. N., Gourley, R., d’Agostino, A., Goodnight, S., Worthen, H. Ann. Allergy, 1970, 28, 378. 79. Aerenlund-Jensen, H., Halveg, A. B., Saunamaki, K. I. Br. med. J. 1971, iv, 406. 80. Tannenberg, A. M., Wicher, K. J., Rose, N. R. J. Am. med. Ass. 1971, 218, 449.

BRACKEN

IT was several years ago that the prediction was first made that many, if not all, cancers would eventually turn out to be due to environmental factors. This forecast receives increasing support each year with the discovery of new types of chemical pollutants or food contaminants which are potent carcinogens in laboratory animals, or which are associated with an abnormally high incidence of a particular cancer in man. Some ten years ago, investigations into the syndrome of acute bovine bracken poisoning led to the discovery that certain constituents of bracken are carcinogenic for rats- and mice.83 Now one of at least two carcinogenic fractions shown to be present in extracts of bracken has been identified as shikimic acid.84 In tests of its carcinogenic properties by chronic administration to mice and by measurement of its ability to cause lethal mutations, shikimic acid has proved to be a very effective carcinogen, comparable in activity to highly potent carcinogens such as aflatoxin and benzpyrene. The rather startling aspect of this finding is that shikimic acid, as an intermediate in the biosynthesis of aromatic arninoacids, is a widespread constituent of a large variety of plants, in contrast to many other carcinogens whose distribution is very limited because they arise as a result of a specialised industrial process 81. McCracken, G. J. Pediat. 1974, 84, 882. 82. Garrod, L. P. Br. med. J. 1974, iii, 96. 83. Evans, I. A., Mason, J. Nature, 1965, 208, 913. 84. Evans, I. A., Osman, M. A. ibid. 1974, 250, 348.