969LEADING ARTICLES

Reversibility of Hypertension

THE LANCETLONDON : : SATURDAY, NOV. 15, 1952

THE reversibility of hypertension is in no doubtwhen the causative disease is self-limited or can becured. Thus in acute nephritis and toxaemia of

pregnancy the blood-pressure returns to normal withresolution of the primary disease ; removal of anadrenal tumour or a diseased kidney may likewise befollowed by return of the blood-pressure to normal;and hypertension occurring in young adults duringperiods of stress may subside spontaneously. The realproblem turns around the reversibility of chronic highblood-pressure. The change from a labile to a fixedlevel is a common sequence in both renal and essentialhypertension, and in many cases fixation is followedby a progressive rise in pressure which may lead to amalignant termination, characterised by papilloedemaand progressive renal failure. The mechanisms offixation of the blood-pressure and of the transitionfrom the benign to the malignant phase are unknown,as indeed are the mechanisms by which both renal andessential hypertension originate ; and until these

processes are understood it seems improbable that anyreliable treatment of hypertension will be devised.Nevertheless certain facts have been established byclinical observation and animal experiment which mustbe taken into account both in the selection of casesfor treatment and in the interpretation of results.

In the first place it is still of vital importance tomake the distinction between essential hypertensionand that due to primary renal disease. This distinctionhas been obscured in the past, and still is insome quarters, by two misconceptions-the first thatessential hypertension is due to renal arteriosclerosis,and the second that the condition we now recogniseas the malignant form of essential hypertension isa manifestation of chronic nephritis. Both these

concepts found a place in the classification of Bright’sdisease by VOLHARD and FAHR,1 who attributed

hypertension in nephrosclerosis to degenerative lesionsof the renal arteries and described malignant nephro-sclerosis as a combination of the benign form andnephritis. KIMMELSTIEL and WILSON 2 first clearlyshowed that nephrosclerosis was a progressive develop-ment during the course of both benign and malignanthypertension and that, in the latter, renal lesions wereslight in the early stages. These observations - werestrikingly confirmed when WILSON and BYROM3

demonstrated by experiment on animals that hyper-tension could produce arterial and parenchymatouslesions in the kidney closely resembling those of

malignant hypertension. This work presentedan admirable opportunity to dispense with thetwo misconceptions which had previously obscuredthe relationship of essential hypertension with thekidney. Unfortunately, however, GOLDBLATT 4 dis-missed the lesions described by WILSON and BYROM

as artefacts and persisted in the view that his experi-ments provided unequivocal evidence on the one handthat essential hypertension is due to renal arterio-sclerosis and on the other that uraemia is an essentialfactor in producing the lesions of malignant hyper-tension. BYROM and DoDSON 5 refuted this argumentwhen they produced arteriolar necroses in the rat

kidney after forcibly raising renal blood-pressure byintra-arterial saline injection. WILSON and BYROMjustifiably concluded that malignant hypertension,with its histological counterpart malignant nephro-sclerosis, was a syndrome which might complicate anyform of hypertensive disease. The value of these

experimental studies in the interpretation of thenatural history of various forms of hypertensiveBright’s disease was emphasised by ELLIS in hisCroonian lectures. 6

It is now common experience that papilloedema,the diagnostic sign of malignant hypertension, usuallysubsides if the blood-pressure can be reduced bysympathectomy or hexamethonium drugs, and thisis true whether the underlying disorder is essential

hypertension or primary renal disease. Elsewhere inthis issue Professor PICKERING and his colleaguesdescribe such a reversal of papilloedema in three casesof pyelonephritis severally treated by nephrectomy,subtotal adrenalectomy, or sympathectomy. In allthree, acute vascular necroses were found in theadrenals and in sections of kidney removed at opera-tion, but the writers had no opportunity to observethe reversal of these lesions. They present the thesisthat therapeutic reduction of blood-pressure can

change malignant hypertension to benign and thatthe benign and malignant courses are merely expres-sive of the severity of the hypertensive processirrespective of the underlying lesion. While this thesisis broadly acceptable there is nevertheless considerableevidence that the level of high blood-pressure cannotalone account for the malignant change. Women

may sustain for half a lifetime a degree of hypertensionwhich in men would almost certainly change to themalignant form in a few years. Similar qualitativedifferences in response to high blood-pressures havebeen observed in animals. It seems likely that thereis some individual susceptibility of the arteries andarterioles which produces an exaggerated vasocon-

strictor response to rise in intra-arterial tension. The

reversibility or otherwise of the process may then wellbe determined by the resulting damage to the renalvessels. PICKERING and his colleagues regard the.successful reduction of blood-pressure in their threecases as evidence against the concept of a viciouscircle (put forward by WILSON and BYROM 7) in whichhypertensive renal vascular lesions perpetuate andaggravate the hypertension. They agree that alter-natively a vicious circle may exist which apparentlycan be broken in the early stages. One cannot overlookthe fact that many cases of unilateral renal diseasecontinue with sustained hypertension after nephrec-tomy, and the clinical features of the malignant phasemay return after an apparent reversal. In essential

hypertension, moreover, a change from the malignantto the benign type for more than a few years isuncommon and even so the blood-pressure usually1. Volhard, F., Fahr, T. Die Brightsche Nierenkrankheit. Berlin,

19142. Kimmelstiel, P., Wilson, C. Amer. J. Path. 1936, 12, 45.3. Wilson, C., Byrom, F. B. Lancet, 1939, i, 136.4. Goldblatt, H. The Renal Origin of Hypertension. Springfield, Ill.,

1948.

5. Byrom, F. B., Dodson, L. F. J. Path. Bact. 1948, 60, 357.6. Ellis, A. Lancet, 1942, i, 72.7. Wilson, C., Byrom, F. B. Quart. J. Med. 1941, 10, 65.

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remains at a high level ; in benign hypertension, onthe other hand, restoration of blood-pressure to normalby sympathectomy is often successful. It is hard toavoid the conclusion that the comparative irreversi-bility of malignant hypertension, whether essentialor renal, is due to secondary renal vascular lesions-i.e., arterial necrosis and endarteritis which produceirreversible renal ischaemia.The experiments, of BYROM and DODSON 8 and

FLOYER 9 have confirmed WiLsoON and BYROM’Sconclusion that persistent hypertension after removalof the ischaemic kidney is attributable to secondarychanges in the opposite kidney. That similar lesionsoccur in the opposite kidney in patients with hyper-tension due to unilateral renal disease is now wellrecognised.10 It is possibly hazardous therefore toclaim reversibility of malignant hypertension withoutfull reference to the underlying cause of the hyper-tension and the possible influence of secondary renallesions. Much confusion still derives from the use of

" malignant hypertension "

as a diagnostic label inprimary renal disease. In view of the terminologicalobscurantism which Bright’s disease produces inmost of its devotees it would be better to speak(though not in the hearing of the patient) of benignand malignant essential hypertension, and in primaryrenal disease to follow the time-honoured tradition of

choosing a name which indicates the primary disorderrather than a late and still somewhat uncertain

complication.

8. Byrom, F. B., Dodson, L. F. Clin. Sci., 1949, 8, 1.9. Floyer, M. A. Ibid, 1951, 10, 405.

10. Allen, A. C. The Kidney. New York, 1951.11. New York Times, Oct. 23, 1952.12. Hammon, W. M., Coriell, L. L., Stokes, J. jun. J. Amer. med.

Ass. 1952, 150, 739 ; Hammon, W. M., Coriell, L. L., Wehrle,P. F., Klimt, C. R. Stokes, J. jun. Ibid, p. 757.

Preventing PoliomyelitisExcITING news of poliomyelitis was given at the

annual meeting of the American Public HealthAssociation.il Dr. W. McD. HAMMON described theresults which he and his colleagues have had in acarefully conducted trial of the protective effectof gamma-globulin in poliomyelitis. 12 Extensivefield tests were made during poliomyelitis epidemics inUtah, Texas, Iowa, and Nebraska in 1951 and 1952.Of nearly 55,000 children, aged from one to elevenyears, half received an intramuscular injection of

gamma-globulin, while the remainder were injectedwith gelatin solution. The solutions looked exactlyalike and strict precautions were taken to ensure

that until all assessments had been made no-oneconcerned with the trial knew which children receivedthe gamma-globulin. There were 64 cases of paralyticpoliomyelitis among the control children, comparedwith 26 among those receiving gamma-globulin.In the first week following the injection of gamma-globulin the degree of protection was barely significant,but HAMMON et al. think that in the late stages of theincubation period gamma-globulin may modify theseverity of the paralysis without preventing it

altogether. During the second week the degree ofprotection increased greatly, for only 3 childrenwho had had gamma-globulin got poliomyelitis,compared with 23 who had had gelatin. This increasedprotection was maintained until the end of the fifthweek; thus, between the second and fifth weeks6 cases occurred in the gamma-globulin group and38 in the controls. True, protection was short-

lived, in spite of the fact that large amounts of gamma-globulin were given : on the basis of body-weight,an average five-year-old child received 7 ml. Never-theless, this is the first prophylactic measure whichhas significantly reduced the incidence of paralyticpoliomyelitis. STOKES et al.13 have suggested thatgamma-globulin, given to children who have been

exposed to the virus of infective hepatitis, may,instead of preventing the disease, modify it in sucha way that a subclinical infection with lastingimmunity results. It may be that a similar effectin this poliomyelitis trial will prolong the period ofprotection in certain individuals ; alternatively gamma-globulin may prevent subclinical infections, so that itsaction would be less favourable in the long run; butit is too early to assess these possibilities. Of course,gamma-globulin has been used before in attempts toprotect children exposed to poliomyelitis ; but this isthe first evidence to suggest that poliomyelitis maytake its place beside measles and infective hepatitisas a disease in which those at risk can be protectedin this way.At the same meeting,14 Dr. H. A. Hows described

the use of an inactivated poliomyelitis vaccine inchildren. It has been well established that monkeyscan be protected against large doses of poliomyelitisvirus by intramuscular injections of an inactivevaccine, and HowE’s experiments are the clinical

application of these findings. The vaccine was

prepared from the brain of an infected monkey,and the brain was treated with formaldehyde toinactivate the virus. Strains of all three serologicaltypes of poliomyelitis virus were incorporated in thevaccine, for injection with one strain gives little

protection against heterologous types. These poly-valent vaccines produced no untoward reactions in6 children to whom they were given, and significantlevels of antibody to the three serological types ofvirus developed in the children’s sera. Serum anti-

body is known to be effective against experimentalpoliomyelitis, and there is also evidence that after

invading the gastro-intestinal tract the virus reachesthe nervous system by way of the blood-stream 15;it is therefore reasonable to suggest that these childrenmay be protected against paralytic poliomyelitis.HowF pointed out, however, that the vaccine mightstill require many modifications in order to increaseits effectiveness and abolish the risk of allergicencephalomyelitis.

These are clearly important steps towards the

prevention of poliomyelitis, but it is probably bestto regard them, for the time being only, as pointersto further research. To protect a large number ofpeople in this way gamma-globulin would be

required in such enormous amounts that we may befaced with the possibility of exsanguinating half thepopulation to protect the rest. The use of inactivatedvaccines on a large scale may raise a similar problem,for one monkey might be needed to provide enoughvirus to vaccinate a single child successfully. Theonly clear way out of this impasse is to use liveattenuated virus vaccines ; here two difficultiesarise-the preparation of attenuated strains of polio-myelitis virus and their testing in human beings-13. Stokes, J. jun., Farquhar, J. A., Drake, M. E., Capps, R. B.,

Ward, C. S., Mills, O., Kitts, A. W. Ibid, 1951, 147, 714.14. New York Times, Oct. 21, 1952.15. Bodian, D. Amer. J. Hyg. 1952, 55, 414.