26

not needed this year, the whole exercise will bevaluable practice for doing it when a really newinfluenza A does finally appear.

Cobalt in Severe Renal Failure

GARDNER,1 SCHLEISNER,2 KASANEN et aI.,3 andGEILL 4 successfully treated the anaemia of renalfailure with cobalt, but all reported side-effects-notably, anorexia, nausea, vomiting, and diarrhoea.According to GARDNER,1 these gastrointestinalsymptoms were dose-related and were uncommonwhen the daily dose, as enteric-coated cobaltouschloride tablets, did not exceed 100 mg a day.Other possible toxic effects, in man or in laboratoryanimals, include tinnitus,l nerve deafness,1 2 skinhypersensitivity, 5 hypothyroidism and goitre,6-9polycythsemia,’° 11 vasodilatation and flushing, 12hypotension, 11 14 changes in pancreatic islet cells, 15cardiomyopathy,16-18 optic atrophy,t9 polyneuro-pathy,20 malignant tumours,21 hyperlipoemia, 22 23diffuse interstitial pulmonary fibrosis,24 2s renaltubular damage ’20 26 and possible precipitation ofangina pectoris.27 In a number of investigations,however, side-effects have been rare and

slight. 10 13 28 The common factor in these mayhave been that the patients had normal renal func-tion, whereas in most other series cobalt had beenused to treat the ansemia of renal failure. Becauseof the gastrointestinal side-effects, cobaltouschloride has usually been prescribed as enteric-coated tablets, to be taken after meals, and varia-tion in absorption could account for some of thedifferences in reported toxicity. 29A number of groups have tried the effect of

1. Gardner, F. H. J. Lab. clin. med. 1953, 41, 56.2. Schleisner, P. Acta med. scand. 1956, 154, 177.3. Kasanen, A., Kulonen, M., Forsström, J. Ann. Med. intern, fenn. 1963, 52,

434. Geill, T. Geront. clin. 1969, 11, 48.5. Browning, E. in Toxicity of Industrial Metals; chap. 13. London, 1961.6 Knss, J P., Carnes, W. H., Gross, R. T. J. Am. med. Ass. 1955, 157, 117.7. Sederholm, T., Kouralainen, K., Lamberg, B. A. Acta med. scand. 1968,

184, 301.8. Little, J. A., Sunico, R. J. Pediat. 1958, 52, 284.9. Washburn, T. C., Kaplan, E. Clin. Pediat. 1964, 3, 89.

10. Davis, J. E., Fields, J. P. Fedn Proc. 1955, 14, 331.11. Hopps, H. C., Stanley, A. J., Shideler, A. M. Am. J. clin. Path. 1954, 24,

1374.12 LeGoff, J. M. J. Pharm. exp. Ther. 1930, 38, 1.13. Perry, H. M., Schroeder, H. A. Am. J. med. Sci. 1954, 228, 396.14 Schroeder, H. A., Perry, H. M. J. Lab. clin. Med. 1955, 46, 416.15. Fodden, J. A. Archs Path. 1956, 61, 65.16. Morin, Y., Daniel, P. Can med. Ass. J. 1967, 97, 926.17. Kesteloot, H., Roelardt, J., Willems, J., Claes, H. H., Joossens, J. V. Circula-

tion, 1968, 37, 854.18. Sullivan, J., Parker, M., Carson, S. B. J. Lab. clin. med. 1968, 71, 893.19. Licht, A., Oliver, M., Rachmilewitz, E. A. Isr. J. med. Sci. 1972, 8, 61.20. Schirrmacher, V. O. E Br. med J. 1967, i, 544.21. Heath, J. C. Br. J. Cancer, 1956, 10, 668.22. Caplan, R. M., Curtis, A. C. J. Am. med. Ass. 1961, 176, 859.23. Caplan, R. M., Block, W D. J. invest. Derm. 1963, 40, 199.24. Coates, E. A., Watson, J. H. L Ann. intern. med. 1971, 75, 709.25. Delahant, A. B. Archs ind. Hlth, 1955, 12, 116.26. Holly, R. G. J Am. med. Ass. 1955, 158, 1349.27. Berk, L., Burchenal, J. H., Castle, W. B. New Engl. J. Med. 1949, 240, 754.28. Holly, R G Obstet. Gynec. 1957, 9, 299.29. Paley, K P., Sussman, E S Metabolism, 1963, 12, 975.

cobaltous chloride, 25-50 mg a day, in patients onmaintenance hxmodialysis.3o-33 BowiE andHURLEY3’ gave cobaltous chloride orally in

aqueous solution, twice a day, in a total daily doseof 25 mg for the first 4 weeks and then 50 mg fora further 4 weeks. Their 14 patients had little

change in haematocrit during the first 4 weeks but,after 8 weeks’ treatment, the 11 who completed thetrial had a 23% increase. There was no evidence ofthyroid or liver dysfunction but 3 patients hadtransient loss of hearing, confirmed by audiometry.Serum concentrations of cobalt, determined by ato-mic absorption spectrophotometry, fluctuated con-siderably. DucKHAM and LEE32 studied 12 anephricpatients on maintenance haemodialysis and gavethem enteric-coated tablets of cobaltous chloride25-50 mg daily for 12 weeks. 6 of 8 patients whocompleted a course of 50 mg a day for 12 weekshad a significant rise in haemoglobin (26-70%) andthen a fall to near the original levels when cobaltwas withdrawn. The haemoglobin rose again in 4patients who had a second course and in 1 patientwho had a third course. The serum-cobalt concen-tration tended to stabilise after 2 months’ con-

tinuous therapy in the range of 40-100 µg/dl, andserum-cobalt fell rapidly when therapy was

stopped. 1 patient failed to complete the coursebecause of nausea and constipation attributed tocobalt, and 1 patient developed slight high-tonedeafness during a second course of treatment, after40 weeks of cobalt therapy. BOWIE and HURLEY31and DUCKHAM and LEE32 conclude that cobaltouschloride has a definite place in the treatment of therefractory anaemia of chronic renal failure.

CURTIs et al. 33 gave enteric-coated cobaltouschloride in a dose of 50 mg per day for threemonths to 23 patients on maintenance hæmodia-

lysis, 8 of whom were anephric. About half had arise in mean haemoglobin of more than 1 g/di(range 1.3-2.6). Side-effects initially seemed

acceptable: 4 patients had nausea and vomitingand in 2 of them treatment was stopped. However,1 patient died of resistant congestive cardiac failurethree months after completing a course of cobalt.Suspecting a cardiomyopathy due to cobalt toxi-

city, CURTIs et al. measured the myocardial cobaltconcentration (by neutron activation analysis) inthis patient and it was 25-80 times greater thanthat in 2 other dialysis patients who had neverreceived cobalt and in 2 other patients who had nothad renal failure. In addition, whole-blood cobaltconcentrations (neutron activation analysis) in di-alysis patients who had been treated 13-20 monthspreviously with cobalt were significantly higherthan in dialysis patients who had not received

30. Edwards, M. S., Curtis, J. R. Lancet, 1971, ii, 582.31. Bowie, E. A., Hurley, P. J. Aust. N.Z.J. Med. 1975, 5, 306.32. Duckham, J. M., Lee, H. A. Q.Jl Med. 1976, 45, 277.33. Curtis, J. R., Goode, G. C., Herrington, J., Urdaneta, L. E. Clin. Nephrol

1976, 5, 61.

27

cobalt. These workers also studied whole-bloodcobalt concentrations prospectively in dialysis pa-tients and normal subjects after cobalt adminis-tration : both groups had prolonged increases inblood cobalt but the blood concentrations weremuch higher in the dialysis patients.How does cobalt work? There is considerable evi-

dence that it leads to increased production of eryth-ropoietin,34 35 but DUCKHAM and LEE’S32 patientswere anephric andCURTIs et al. 33 found no signifi-cant difference in the response to cobalt between

anephric patients and those with kidney remnants.Thus, in anephric patients it would have to be pos-tulated that cobalt acts through extrarenal sourcesof erythropoietin. As to the mechanism by whichcobalt induces erythropoietin production, one

suggestion is suppression of cellular energy metabo-lism by inhibition of sulphydryl groups of some oxi-dative enzymes, resulting in diminished oxygen uti-lisation by the tissues. NEAS and NEUWIRT36 pointout that, if this hypothesis is correct, then erythro-poietin production induced by cobalt should be tosome degree independent of tissue oxygen tension.They were unable to confirm this in the rat, andthey also found no difference in the oxyhæmoglobindissociation curves in control and cobalt-treatedanimals. NEAS and NEUWIRT36 suggest that cobaltmay act by producing local ischaemia of kidneyreceptors controlling erythropoietin production orby altering the sensitivity of these receptors.ADAMSON and HERBERT37 have also reported thatcobalt stimulates globin synthesis in reticulocytes.

Finally, how does the treatment stand? Unstea-dily. CuRTIs et al. 33 take the view that, because thetherapeutic gains are slight and the long-termeffects imponderable, cobalt should not be used inthe anaemia of chronic renal failure. DUCKHAM andLEE remain squarely in the opposite camp.38

Macrophages v. CancerSCHWARTZ39 points out that BURNET’S theory of

immune surveillance has been in danger of becom-ing a fact. Pragmatism comes into the matter:

several measures adopted in the treatment ofcancer only make sense against a background ofimmune surveillance. For example, the use ofB.C.G. as adjuvant therapy is intelligible on the un-

34 Goldwasser, E., Jacobson, L. O., Fried, W., Plzak, L. F. Blood, 1958, 13,55.

35 Fisher, J E, Langston, J. W ibid. 1967, 29, 114.36 Nečas, E., Neuwirt, J. in the Regulation of Erythropoiesis and Haemoglobin

Synthesis (edited by T. Travnicec and J. Neuwirt), p. 91. Prague, 1971.37 Adamson, S D, Herbert, E. ibid. p. 373.38 Duckham, J. M., Lee, H. A. Lancet, June 19, 1976, p. 1350.39 Schwartz, R. S. New Engl. J. Med. 1975, 293, 181.

derstanding that there is an immune defence mech-anism against cancer which is promoted by B.c.G.,a known immunostimulant. This justification ofB.c.G. therapy could be correct, and one can arguethat, if the treatment works, the logic behind itbecomes irrelevant. Such an attitude is dangerous,firstly because it is barely distinguishable from thatof the witch-doctor, and secondly because, if forsome reason the mysterious method ceases to work,the course of further action may be unclear.The notion of immune surveillance against

cancer is losing support. In 1971 the 7th volume ofTransplantation Reviews was entitled ImmuneSurveillance against Neoplasia. Six years later, vol.28 of the same journal is called Experiments andthe Concept of Immunological Surveillance. Thissecond title gently veils a range of experimental evi-dence which the editor feels is inimical to the

theory. In immunologically inadequate organismsthe most frequent neoplasms are those of the lym-phoid system and the argument, broadly, is thatthis observation is not predicted by the surveillancetheory. These lymphoid neoplasms could in factarise as a consequence of some imbalance in a regu-latory process. In particular, it could be that the re-sponses to antigenic stimuli are exaggerated mitoti-cally in the absence of the usual numbers of

responding cells. There arises thus a heightenedchance of malignant change within the depletedlymphoreticular complex. In addition it is arguedthat the lymphoid system could be thought of aseffecting surveillance, in that it might regulate thegrowth of populations of potentially oncogenicviruses. Of course, these and other arguments arenot going to topple the immune-surveillance theoryof cancer. The important thing is that at last thetheory is being appraised by experiments designedto find exceptions. This as SCHWARTZ points out,following PoPPER,40 is scientifically much morehealthy than the unquestioning attempts to provethe theories which have so far prevailed.

Not surprisingly, some tumour immunologists,fearing collapse of the pillar of their faith, are striv-ing to provide alternative props.. Thus ALEX-ANDER41 proposes his favourite cell, the macro-

phage, as the mediator of surveillance, rather thanthe more specifically immunologically active lym-phocyte. The background to ALEXANDER’S sugges-tion is relevant. Firstly, tumours can contain,among other normal cells, macrophages. This is

particularly true of melanomas in both mice andmen. These invading host cells have not often beenaccurately quantitated, particularly in humantumours. During radiotherapy or chemotherapy oftumours the host cell composition can alter, butagain neither the quantity nor the quality of hostcells has been determined in an adequate number

40. Magee, B. Popper. London, 1973.41. Alexander, P. Br. J. Cancer 1976, 33, 344.