645

THE MECHANISM OF PROTEINURIA

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THE LANCET

LONDON: SATURDAY, MARCH 25, 1933

ALTHOUGH " albuminuria " is common enough,and has long been the subject of careful clinicalobservation, the mechanism whereby protein canescape from the blood into the urine has not yetbeen adequately explained ; indeed, relativelylittle sustained effort has been made of late yearsto elucidate this problem. It is known, of course,that egg-albumin, if introduced into the circula-tion of a mammal, will be excreted in the urine,and this effect has usually been explained by thehypothesis that the kidney acts as an eliminatorof foreign substances from the blood, butCUSHNY in his monograph on the excretion of theurine observed that the glomerulus usually appearedto be impermeable to colloid substances, andconcluded that the passage into the urine of

proteins, such as egg-albumin, was dependentupon glomerular damage. Very little advancehas in fact been made in our knowledge of thisaspect of renal function since the work of POSNERat the end of last century.

In a recent contribution to THE LANCET 1 Mrs.PHYLLIS KERRIDGE, Ph.D., and Dr. L. E. BAYLISSattacked the view that the excretion of proteinsby the normal kidney depends on whether theyare foreign to the body. And on the basis of anumber of perfusion experiments with the pump-lung-kidney and with intact anaesthetised animalsthey have been able to show that the facility withwhich any protein passes through the glomerulusdepends upon the size of its molecule. Theirestimates of the molecular weights of the differentproteins used have been taken from BvEDRRG’sfigures. Molecules with a weight below 68,000,-such as egg-albumin, gelatin, and Bence-Jones’s

protein are excreted, while those with a weightabove 68,000, such as the serum proteins, are

retained. As promised in their first communica-tion a full account of the work has now been

published elsewhere2 with the collaboration ofDr. DOROTHY S. RUSSELL, who has examined

histologically a number of the kidneys used inthese experiments. Those interested in the subjectshould refer to this paper for details. Withoutlosing sight of the fact that alterations in capillarypermeability are doubtless responsible for protein-uria in some diseases of the kidney and of thecardiovascular system, it is clear that a good casehas been made out for a purely mechanical basisof proteinuria in the normal kidney. Both physio-

1 THE LANCET, 1932, ii., 785.2 Jour. of Physiol., 1933, lxxvii., 386.

logically and histologically there was no evidenceof any glomerular damage associated with the

passage of the smaller protein molecules, such asegg-albumin, into the urine. But lest the reac-

tionary-minded should still argue that damage mayyet exist that eludes microscopical examination,an interesting observation by these investi-

gators may be quoted which seems to disposeof this objection. It happens that gelatin,in distinction to other proteins, is not pre-cipitated by trichloracetic acid. The passageof gelatin into the urine in these perfusion experi-ments was detected by means of picric acid, and theaddition of trichloracetic acid caused no further

precipitate such as would be anticipated if the

glomerular capillaries had sustained any injurythat caused an increase in their permeability.The replacement by this newer mechanical

hypothesis of the older teleological theory thatascribed an almost uncanny power of discrimina-tion to the renal glomerulus will be welcomed asan advance in our conception of renal function.It will doubtless be asked what light such a theorymay throw on the question of clinical albuminuria.It is clearly desirable that the physical propertiesof the proteins that are excreted in such disordersas cardiac failure, nephritis, and so on should beinvestigated anew. An encouraging start in thisdirection has already been made by E. ANDREWS,W. A. THOMAS, and W. F. WELKER,3 who find thatnephritic serum, though poorer in proteins thannormal serum, has greater hydrophilic properties,while the urinary proteins show an abnormallyhigh degree of dispersion and will readily passthrough a collodion membrane. The proteinsexcreted in nephritis appear therefore to differ fromthe normal blood proteins. On the basis of their

experiments these workers suggest that alterationsin the mineral salt balance result in a pathologicalescape of tissue proteins into the circulation innephritis, with the formation of protein complexespossessing a smaller molecular aggregation or ina higher state of dispersion than is normallyassociated with the serum proteins. This, thoughadmittedly pure theory, converges in an interestingway towards a possible common ground with thetheory of KERRIDGE and BAYLiss. The investi-

gation of various types of nephritis from this

angle may be expected to throw valuable lighton the disturbances of metabolism that occur in

Bright’s disease.

A TEST OF TELEPATHYBELIEF or disbelief in the possibilities of telepathy

and feats like water-divining seems to be determinedby temperamental rather than intellectual influ-ences. To some people belief in them is a clingingto the superstitions of a pre-scientific age ; to somethey offer a field of research that may ultimatelyenlarge the scope of science ; to some they give apleasing proof of the impotence of science to under-stand certain phenomena the existence of which itconveniently denies. Perhaps it is asking too much

3 Arch. Internal Med., 1929, xliii., 445.

646

of mankind to hope for a final decision and cessationof argument, but it is not too much to ask that anyserious investigation should take into account allthe pitfalls, statistical and psychological, that maylurk beneath the simplest-looking and most con-vincing observations.

Incidents of "

premonition " or of knowledgeof events happening beyond the individual’s ken,and subsequently found to be true, are, as everyoneknows, by no means rare. The difficulty in

assessing their value as evidence of telepathy,or of some other psychic power, lies in the absenceof any means of measuring the probability thatthey are not’ due to coincidence. A commonexample of premonition in the war period was thefeeling of a mother that her son was in dangerand calling for her help, and the subsequentnews that he was killed at that hour. But itis obvious that innumerable mothers must havehad the same feeling at one time or another duringthe period of the war, and it is only when thethought and the subsequent news coincide thatthe premonition is remembered and recorded.In such matters the common error of recordingthe " successes " and ignoring the " failures"is at its highest. Another test of telepathycommonly adopted is that in which one personendeavours to convey to another " telepathically

’9

some object of fact which he has in his mind.Such a test, it will be remembered, was carried outa few years ago under the auspices of the B.B.C.In these tests also we do not know the underlyingprobabilities, or in other words what proportionof right answers are likely to be due only tocoincidence.

It was this suggestive type of test that was

employed by the wife of UPTON SINCLAIR whosebook on this problem was discussed in our columnsthree years ago’ The general plan of the experi-ments was that a man agreed to make a drawingof any object he might select at random and thento sit gazing at it and concentrating his entireattention upon it for a period of from 15 to 20minutes. At the same agreed hour Mrs. SINCLAIRwas lying 40 miles away in semi-darkness with hereyes closed, employing a system of mental con-centration. " As a result she took pencil and paperand wrote, with the date, in six words exactlywhat the drawing would be found to be. Andso it was." UPTON SINCLAIR gives 65 drawingswhich he calls successes and about half of 155which he called partial successes. This number,he says, is too great for coincidence. On theother hand, apart from the probability problemsinvolved, another factor has crept in here-thesubjective factor ; for someone must decide whatis a success, what is a partial success, and whatis a failure. Dr. E. E. FREE argues that whilethere are many reported experiments of this type,suggestive of the possibility of telepathy, there arenone which could be called complete and satis-

factory proof. In an article in the Scientific,4nwrican (March, 1933) he proposes a simpletest in which he asks readers to participate. The

1 See THE LANCET, 1930, ii., 252.

experiment merely consists of two persons makinga large number of throws with an ordinary die.The " transmitter " looks at the number throwneach time and concentrates upon it; the " per-cipient " who is blindfolded states the number.The reply is recorded, without comment, as rightor wrong ; 500 such throws, it is reckoned, canbe made in one hour-though but seven secondsfor a shake of the die, a throw, the thought trans-ference and the recording of the reply, seems

somewhat too little. If a large number of suchsets are obtained it will become clear whether thenumber and distribution of correct guesses differsfrom that to be expected from the theory ofchances. If it does not, then there will be pre.sumptive evidence that readers of the scientificAmerican (or rather, a

" selected " group withtime and inclination for such tests) do not as aclass possess telepathic ability. At the same time

provision is made to get in touch with those,if any, whose results do suggest more than theoperation of mere chance. The working out of thechance distribution may, eventually, prove some-what more difficult than may seem at first sight,owing to the fact that ordinary commercial diceare on the average not true, and tend to recordan excess of high numbers.Such attempts to transfer the tests of telepathy

to experiments in which the underlying probabilitiesare known are not new, as Dr. FREE realises.Tests have been made with playing cards, oneperson attempting to " send " and another

attempting to " receive " the names and suits of

cards turned up at random. Many interestingexamples of these tests are to be found in the workof JOHN COOVER,2 who concluded that " notrace of an objective thought-transference isfound either as a capacity shared by our normalreagents in general or as a capacity enjoyed inperceptible measure by any of the individualnormal reagents." The results of experimentswith ten " psychics " (reputed to be speciallygifted with a power of telepathy or clairvoyance)seem to differ in no essential respects from theresults of the experiments with normal reagents.Some of these results have been discussed fromthe statistical aspect by the late Prof. EDGE-WORTH.3 The latter found that the number of" successes " in a group of experiments was

certainly greater than would be expected by merechance ; yet in a control group in which the agentdid not endeavour to " transmit " the card but the

recipient guessed it, the number of successes waslikewise excessive. " What if the explanation,"writes Prof. EDGEWORTH, " should prove to bethe same for both phenomena-namely, the

impossibility of realising ideal randomness, the

tendency of law to recur however much we tryto expel it by instruments of chance." The

marriage of telepathy and the theory of probabilitymay still be unproductive of the convincing proofDr. FREE seeks,

2 Experiments in Psychical Research at Leland StanfordJunior University. By John Coover, Stanford University.1917. Pp. 641.

2 Jour. Roy. Stat. Soc., 1919, lxxxii., 222.

647TWO VIEWS OF PEPTIC ULCER

THE NATURAL HISTORY OF RHEUMATICFEVER

NEARLY a hundred years ago Latham wrote of theneed for better clinical control of the various methodsof treatment advocated for acute rheumatism, anddespite other advances since that time the needremains urgent to-day. For this reason a group ofworkers in New York have been studying a seriesof cases in which all the usual antirheumatic drugswere withheld in order to see what was the naturalcourse of the untreated disease. Actually every carewas taken to prevent pain and discomfort-by placingthe patients in special beds, by protecting painfuljoints with cotton-wool and cradles, and by admini-stration of codeine. It is also stated that a specialdiet was given, efforts were made to force fluids,and " when infected foci were found every effort wasmade to eradicate them." Under these conditionsthe progress of the disorder was investigated veryelaborately. A detailed history was obtained upona special form, members of a patient’s family wereinterviewed, and the home was visited by a specialmedical social worker. The pulse-rate and rectaltemperature were taken every four hours. A completeblood count was done on admission, twice a weekduring the acute stage, and once a week up to discharge.An electrocardiogram was taken at similar intervalsor even daily if there were acute cardiac complica-tions. Blood cultures were made in all cases at

frequent intervals, skin tests with streptococcalfiltrates were carried out, the heart was radiographedas soon as possible after admission, and X rays werealso used to investigate the teeth, nose, throat, andaccessory sinuses. Notes were made at least once

daily by clinical observers.During the two years of this comprehensive investi-

gation 162 patients with acute rheumatic fever werestudied. Of these 50 were treated with salicylatesor vaccine and were not included in the presentsurvey, which comprised 105 who had no form oftherapy which might be regarded as specific, and noantipyretic drug. They were considered in three

groups, all having active disease : those with poly-

1 Graef, I., Parent, S., Zitron, W., and Wyckoff, J.: Amer.Jour. Med. Sci., Feb., 1933, p. 197.

arthritis with either no heart involvement or oldcardiac trouble which was inactive; those with chorea;and those with a history of repeated rheumaticinfection and advanced structural heart disease.Actually only 47 patients remained in hospital longenough to fulfil certain conditions laid down as tothe cessation of activity, the remainder leaving forvarious reasons. ’ The age-distribution of these 47

patients was as follows : under 20 years, 18 ; between20 and 29 years, 11 ; between 30 and 39 years, 14;and between 40 and 49 years, 4. They were distributedin the three groups outlined above, with 29 in thepolyarthritis group, 6 in the chorea group, and 12in the carditis group. The actual clinical resultsin this total of 47 cases are set out in great detail.Comparing these patients with another series describedby H. F. Swift, in which drugs were used against therheumatic process, the present authors concludethat the elimination of such remedies did not prolongthe illness. Without antipyretics the temperatureappeared to subside spontaneously ; as a rule itbecame, and remained, normal after but a singlecycle of fever. In 22 out of the 29 patients withpolyarthritis the joint complications subsided,untreated, in a week, and recurrences, which wereseen in half the cases, affected fewer joints,were less severe, and were of shorter durationthan the initial attacks. Cases were encounteredin which spontaneous subsidence of arthritis wasas abrupt and complete as when salicylates wereused.

Variations in the P-R interval noted on the electro-cardiogram were wide and inconstant and did notappear very different from those seen in patientswho had had salicylates. Tachycardia, like the fever,in general appeared to subside spontaneously. Therewere six deaths in the series, five from cardiac failurein association with active carditis, and one withpericarditis and profound toxaemia with a rapiddownhill course from the onset. Unfortunately studiesof the sedimentation-rate were not made, for themethod only became known to the authors after thework had been begun ; but their studies seem tohave been sufficiently exhaustive to justify theconclusion that " in adolescence and adult life theacute manifestations of rheumatic fever tend tosubside spontaneously."

ANNOTATIONSTWO VIEWS OF PEPTIC ULCER

THE many factors that may promote peptic ulcera-tion can be classified as general or local: under theone heading we have all the circulatory, toxic,chemical, and constitutional variations which are

suggested as exciting or predisposing causes, whileunder the other there are several possible sources ofdamage to the mucous membrane. The part playedby dietary indiscretion in causing such damage haslately been considered by Prof. R. Ehrmann,l ofBerlin, who has analysed some 7000 cases of pepticulcer and also about 800 autopsies. He notes thatduring the years 1917-24 there was a graduallyincreasing incidence of ulcer, followed by a con-

spicuous diminution. This rise during and just afterthe late war Ehrmann attributes to the unsatisfactorydiet of those times, which he regards as very favour-able to the production of local gastric injury. Hepoints out that at this time the diet was voluminous,coarse, and lacking in fat, so that the stomach was

1 Deut. med. Woch., Feb. 3rd, p. 166.

likely to be unduly distended. According to hisview, peptic ulcers arise, like wounds of the skin,through injuries, haemorrhages, or necroses, particu-larly situated along the Magenstrasse-i.e., thelesser curvature-and are primarily due to faultydiet. Gastric ulcer he describes as a disease of the" seven lean years" in contrast to cholelithiasiswhich he regards as a disease of " fat years."

L. W. Kohn on the other hand, assumes thatvarious factors are responsible, and emphasises thesignificance of local thrombosis of gastric arteries,comparing them with the changes seen in thrombo-angiitis obliterans. On these lines he has treateda number of patients with intravenous injections ofsodium citrate, in the hope of improving the localblood-supply to the stomach. In his studies, whichare not reported in detail, he has noted an increasedclotting tendency of the blood in ulcer patients,and he considers that sodium citrate has the ultimateeffect of lessening coagulation, in spite of some

2 Med. Jour. and Record, Feb. 1st, 1933, p. 103.