739

:l6iE III--COMPARISON OF CO DOSE, FILTER-NICOTINE RATIOS,CORRECTED CO DOSE, AND COHb LEVELS

patterns as shown by a decrease in butt lengthsand a rise in observed/expected filter-nicotineratios. These changes in smoking patterns can beexpected to effect the CO dose. In an attempt to

:ake these changes into account, we made a cor-

rection for the CO dose by multiplying the expectedCO dose by the observed/expected filter-nicotineratios (table III). The " corrected " CO dose shows

virtually’no change between medium and low periodsand correlates well with COHb levels, which were alsounchanged. The correlation is less close on changingIO very-low cigarettes, when the corrected CO dosefell by 23 % and COHb levels by 39 %. The correctionof CO dose by the use of observed/expected filter-nicotine ratios thus provides a partial but not completecorrection for the alterations in CO dose producedby changes in smoking patterns.These results indicate that a change to very low

tar and nicotine cigarettes may reduce the hazardsof smoking, since both the CO and nicotine dose arereduced. Unfortunately all subjects rated these cigar-ettes as unsatisfying. Over recent years cigarettemanufacturers have gradually reduced the tar andnicotine yield of cigarettes. Sixty of the ninety brandswhich were in both the first (April 1973) and thesecond (February 1974) Government league tableshave a lower tar yield. This suggests that a gradualreduction in the tar/nicoline content may be accept-able to the average smoker, and it is hoped thatmanufacturers will also take steps to reduce thecarbon-monoxide production of cigarettes.

, These results were obtained over a three-week

period, but a long-term study is necessary to see

whether this effect on smoking pattern persists. A

progressive reduction to lower-nicotine cigarettesmay enable some smokers who are unable to stopsmoking to accept very low tar/nicotine brands, thusreducing the risk to their health.We thank all the subjects who took part in this trial;

Dr M. W. McNicol for advice; and to Mr M. Tate, of GallaherLtd., for supplying the product data on the cigarettes and foranalysis of filter-nicotine.

Requests for reprints should be addressed to R. W. S.

REFERENCES

1 Royal College of Physicians. Smoking and Health Now; p. 132.London, 1971.

2. Ashton, H., Watson, D. W. 1970. Br. med. J. 1970, iii, 679.3 Frith, C. D. Psychophormocologia, 1971, 19, 188.4 Russell, M. A. H. Lancet, 1974, i, 254.5 Waingrove, S., Horn, D. Natn. Cancer Inst. Monogr. 28, p. 29. 1968.6 Astrup, P. Ann. intern. Med. 1969, 71, 426.7 Aronow, W. S., Rokaw, S. N. Circulation, 1971, 44, 872.8 Wald, N., Howard, S., Smith, P. C., Kjeldsen, K. Br. med. J.

1973, i, 761.9 Willits, C. O., Swain, M. W., Connelly, J. A., Brice, B. A. Analyt.

Chem. 1950, 22, 430.10 Samfield, M. Tobacco International, Sept. 28, 1973, p. 26 and p. 28.

EFFECT OF RENAL TRANSPLANTATION

ON URÆMIC NEUROPATHY

M. M. IBRAHIM

J. M. CROSLANDL. HONIGSBERGER

A. D. BARNESP. DAWSON-EDWARDS

C. E. NEWMAN

B. H. B. ROBINSON

Department of Neurophysiology and Renal Unit,Queen Elizabeth Hospital, Birmingham B15 2TH

Summary Of 6 patients with severe uræmic

neuropathy 4 responded rapidly to

cadaveric renal transplantation, improvement some-times preceding the onset of diuresis. Of the 2 others,graft rejection was associated with deterioration inone and with failure of response in the other. Electro-

physiological studies in 10 further patients with sub-clinical neuropathy confirmed that early improvementin nerve conduction may follow cadaveric trans-

plantation and is not directly related to the establish-ment of an adequate glomerular filtration-rate. Lossof a metabolic function of renal tissue not dependenton the secretion of urine is postulated as partly orwholly responsible for uræmic neuropathy. Pro-

gressive neuropathy in terminal uræmia is an

indication for early transplantation.

Introduction

CHRONIC renal failure may be complicated bypolyneuropathy. This disorder has become more

significant because of the prolongation of life by long-term dialysis. The clinical and pathological featureshave been described. 1-4 The neuropathy is sensori-

motor, although either sensory or motor features

may predominate. The condition develops in chronicrenal failure of long duration, and pathological changescomprise loss of the myelin sheath and axonal de-generation. Terickhoff et al .2 believed there to beno correlation between the degree of neuropathy andthe degree or duration of renal failure. Neuropathyis most commonly sensory, but the onset may be

explosive and progress to a disabling motor neuro-pathy. Milder sensory changes usually improve withdialysis; but deterioration may occur. Motor changesare particularly slow to improve even with frequentdialysis. Funck-Brentano et al.1 and Dinapoli et al.6have reported improvement in urasmic neuropathyfollowing successful renal transplantation, but Merrillet al.1 were less optimistic. More recently Boltonet al.1 have reported significant improvement in 10

patients, several with severe disability, following renaltransplantation. They were able to report bothclinical and electrophysiological improvement of

sensory and motor neuropathy.Our experience suggests that uraemic neuropathy

may be dramatically improved by renal transplanta-tion, and we report here the effects of cadaveric

grafting in 6 patients with disabling neuropathy whichhad developed despite regular hxmodialysis. In 14

patients receiving renal allografts nerve-conductionstudies were performed before and at intervals aftertransplantation to establish objective evidence of therate of improvement in nerve conduction and itsrelationship to graft function.

740

Patients and Methods

All patients underwent cadaveric renal transplantationat the Queen Elizabeth Hospital, Birmingham, followingpreliminary hxmodialysis in this unit or in one of threeother units. Clinical data on the 6 patients with overtneuropathy are summarised in the accompanying table.

Dialysis was performed three times weekly for eight hoursusing ’ Travenol Ultra Flo II’ coil dialysers. 2 patientshad also had prolonged periods of dialysis with the modifiedKiil dialyser.

Following transplantation a standard immunosup-pressive regimen of prednisolone and azathioprine wasfollowed.

Nerve-conduction VelocityNerve-conduction Velocities (N.C.V.) were measured

preoperatively and at varying periods up to six monthsafter renal transplantation in 2 of the subjects with signsof peripheral neuropathy and in 12 uraemic patients with-out overt neuropathy. Measurements were made witha ’ Medelec MS6 ’ apparatus with bipolar needle electrodes.Motor and, wherever possible, antidromic sensory-motorconduction velocities were measured. The ulnar nerve wasstudied in the arm, the medial popliteal nerve in the leg.

Results

Effect of Transplantation on Clinical NeuropathyThe effect on clinical neuropathy is summarised

in the table. In 3 patients with severe disability therewas early and striking improvement after trans-

plantation. In 2 of these patients subjective improve-ment occurred within two weeks, and objectiveimprovement in neurological signs was evident withinone month. In these 2 patients the early improvementpreceded significant diuresis from the graft. In case 4,three transplants were acutely rejected and no

improvement followed. In the 2 remaining patientsearly subjective improvement, and, in 1 of these someobjective motor improvement, relapsed with the onsetof graft rejection at three months and two months,respectively.The following case report illustrates the rapid

clinical improvement which may follow transplanta-tion.

CASE 1-A man, aged 34, was found to be ursemie in1969 as a result of chronic glomerulonephritis. In

October, 1970, rapidly progressive weakness of the legsdeveloped; creatinine clearance 3 ml. per minute andblood-urea 500 mg. per 100 ml. Thrice-weekly haemo-dialysis was started with coil dialysers for twenty-fourhours per week. Muscle weakness progressed and beganto involve his hands even though the total dialysis-time wasincreased to thirty-six hours per week. By June, 1971, hewas unable to stand and could not hold a pen to write. Acadaveric renal transplant was performed. Six days laterhis grip improved sufficiently to write letters, and on theeleventh postoperative day he was able to walk with a, Zimmer’ frame. At this time there was no significanturine output from the transplant and he was maintainedon regular dialysis. Diuresis became established on thetwentieth postoperative day, and steady improvement inmuscle power continued. Within six weeks he was walkingunaided and deep tendon reflexes, previously absent, hadreturned. One year later he was leading a normal life.There remains residual muscle wasting in the lower legs,but power is good and no sensory loss is detectable. Serum-creatinine is 1-4 mg. per 100 ml. and blood-urea 31 mg.per 100 ml. Unfortunately in this patient serial studiesof conduction velocities were not made in the early stages.In July, 1971, after the transplant, motor and sensoryconduction velocities were somewhat slowed but havesince returned to normal.

Effect of Transplantation on Nerve-conductionVelocity

Preoperatively 12 of the 14 patients had electro-

physiological evidence of neuropathy, only 2 havingconduction velocities within normal limits.The degree of neuropathy, measured either clini-

cally or electrophysiologically, was unrelated to the

degree or duration of renal failure or dialysis. The

change involved both upper and lower limbs, but

predominantly the latter.Successful transplantation was usually followed by

a definite increase in the conduction velocities of bothmotor and sensory nerves in those patients withslowed velocities. In those patients with normal

peripheral-nerve function, no change was producedby transplantation. There was no apparent relation-

ship between the improvement in conduction velocity

DATA ON 6 PATIENTS WITH OVERT NEUROPATHY

741

Fig, 1-Serial ulnar-nerve conduction velocities after renaltransplantation.Mean normal values (metres/sec.): motor 59-9 (s.D. 57);

sensory 55-2 (S.D. 3-5).

and the improvement in overall kidney function, butwith rejection of the transplant the conduction velocitytended to slow. In the early post-transplant periodthis change could coincide with the earliest clinicalevidence of rejection. With acute rejection of thegraft soon after transplantation, nerve-conduction

velocity does not improve at all. The time scale and

degree of change in this velocity in 12 patients isshown in fig. 1.The increase in velocity can be pronounced within

a few days of allografting and before any significantrenal excretory function has been established. Fig. 2shows the rapidity of improvement in a patient withclinical neuropathy (case 6 in the table) in relationto onset of renal function. He subsequently rejectedhis transplant with relapse of neuropathy.

Discussion

Our results confirm the earlier reports that urxmic

polyneuropathy may be improved by a successful

Fig. 2-Case 6: changes in ulnar-nerve conduction velocities,urine output, and serum-creatinine following cadaverictransplantation.

renal allograft, and agree with the more recent studiesof Bolton 8,9 indicating that this improvement may befunctionally complete and accompanied by compar-able improvement in electrophysiological measure-

ments. The remarkable finding in the ’present studyhas been the rapidity of the improvement in mostpatients. In several patients subjective phenomenasuch as parxsthesix and, to some extent, muscleweakness have improved within a few days of trans-plantation, and in 2 patients even objective signssuch as reappearance of previously absent deeptendon-reflexes have preceded establishment of satis-factory renal-allograft excretory function. Unfortu-

nately, serial and frequent measurements of con-

duction velocity were not made in the early patientsin the series, but subsequent studies have confirmedthe clinical impression that conduction velocity isnot directly related to the level of glomerular filtrationand indeed improvement may precede the onset ofgraft function, which is often delayed in cadaveric

transplants as a result of ischasmic damage.The search for the agent responsible for uraemic

polyneuropathy has been directed to the possibilitythat some factor is retained by the failing kidney asa result of loss of excretory function. Lonergan et al.10have reported the presence of a circulating inhibitorof red-cell transketolase in urxmic plasma, and sincethis enzyme may also have a role in peripheral-nervemetabolism they have suggested that this low-

molecular-weight inhibitor may be related to neuro-pathic changes. The correlation of this factor withthe presence of neuropathy has not been established.Support for the concept of a dialysable toxic factorhas come from Jebsen et al.11 who have suggestedthat neuropathy developing during maintenance

dialysis is an indication for increasing dialysis-time.Babb et al.12 have proposed that the responsiblesubstances are of intermediate molecular weight(" middle molecules ") which do not easily cross thedialysis membrane. Prevention or reversal of neuro-

pathy would then depend upon giving adequatedialysis-time relative to the effective membrane-surface area, to overcome resistance to transfer ofthese molecular species.We have observed reversal of neuropathy by pro-

longed and frequent dialysis, but the process hasbeen slow, taking months and years rather than daysand weeks.

The rapidity of change in nerve-conduction velo-city after allografting is surprising. Dayan et a1.4

suggested that the early neuropathic changes are theresult of some agent damaging the Schwann cells, andBolton et al.11 concluded that the recovery processconsists in remyelination followed by slower recoverydue to axonal regeneration. Our observations suggestthat there is an agent (or absence of some necessaryfactor) causing functional interference with nerve

conduction in urxmic subjects, and that the effectof this agent is reversed by the presence of perfusedviable renal tissue. This is not necessarily the factorresponsible for the longer-term recovery of the nerve-fibres themselves.

The rapid reversal of functional neuropathic

742

changes before the establishment of effective renal-allograft urine output suggests that the neuropathycannot be simply the consequence of retention oftoxic substances as a result of loss of glomerularfiltration. These early changes in peripheral-nervefunction following renal allografting may be the result,not of the excretion of " middle molecules " previouslyretained, but of the restoration of a metabolic functionof the kidney, either synthetic or degradative, as yetunidentified. The absence of any improvement inneuropathy when acute rejection of the graft takesplace is evidence that healthy, adequately perfusedrenal tissue is necessary for recovery and confirmsthat the early changes are not due to the immuno-suppressive regimen. The kidney is already knownto function as an endocrine organ, producing erythro-poietin, 1,25-dihydroxycholecalciferol, and renin.Renal tissue has other metabolic functions such as

the degradation of some polypeptides-e.g., insulin.Remission of Fabry’s disease follows restoration ofthe missing metabolic pathway by renal transplanta-tion. -

The finding by Clements et al.13 that plasma-myoinositol levels are raised in uraemic subjects couldat least partly explain our observations. This sub-stance is a hexitol which is normally oxidised to

D-glucuronate. In the rat the major site for thisoxidation is the kidney. Nephrectomy abolishes theformation of 14CO2 from administered 14C-labelledmyoinositol. In rats sciatic motor-nerve conduction

velocity was reduced by feeding them with myo-inositol. Although myoinositol is in part excretedin the urine and is slowly removed by dialysis, itsrenal metabolism may be relevant to ursemic neuro-

pathy and the effects of transplantation, and meritsfurther study.We suggest that, in view of the disabling con-

sequences of urxmic neuropathy, the appearance ofclinical signs of polyneuropathy is an indication for

early renal transplantation rather than prolongeddialysis.

Requests for reprints should be addressed to B. H. B. R.

REFERENCES

1. Ashbury, A. K., Victor, M., Adams, R. D. Archs Neurol. 1963, 8,413.

2. Tenckhoff, H. A., Boen, F. S. T., Jebsen, R. H., Spiegler, J. H.J. Am. med. Ass. 1963, 192, 1121.

3. Arabella, R., Blondeel, N., Roguska, J., Walker, C., Simon, N. M.,Del Greco, F. ibid. 1967, 199, 362.

4. Dayan, A. D., Gardner-Thorpe, C., Down, P. F., Gleadle, R. I.Neurology, Minneapolis, 1970, 20, 649.

5. Funck-Brentano, J. L., Chaumont, P., Vantelon, J., Zingraff, J.Nephron, 1968, 5, 31.

6. Dinapoli, R. P., Johnson, W. J., Lambert, E. H. Mayo Clin. Proc.1966, 41, 809.

7. Merrill, J. P., Hampers, C. L. New Engl. J. Med. 1970, 282, 953.

8. Bolton, C. F., Baltzan, M. A., Baltzan, R. ibid. 1971, 284, 1170.

9. Bolton, C. F. Electroenceph. clin. Neurophysiol. 1973, 34, 829 (B).10. Lonergan, E. T., Semar, M., Sterzel, R. B., Treser, F., Needle,

M. A., Voyles, L., Lange, K. New Engl. J. Med. 1971, 284, 1399.

11. Jebsen, R. H., Tenckhoff, H., Honet, J. C. ibid. 1967, 277, 327.

12. Babb, A. L., Popovich, R. P., Christopher, T. G., Scribner, B. H.Trans. Am. Soc. artif. intern. Organs, 1971, 17, 81.

13. Clements, R. S., De Jesus, P. V., Winegrad, A. I. Lancet, 1973, i,1137.

SINGLE-DOSE DOXYCYCLINE TREATMENTOF LOUSE-BORNE RELAPSING FEVER

AND EPIDEMIC TYPHUS

P. L. PERINES. AWOKE

D. W. KRAUSE

J. E. MCDADE

U.S. Naval Medical Research Unit No. 5, P.O. Box 1014,Addis Ababa, Ethiopia

Summary 26 patients with louse-borne relapsingfever (L.B.R.F.) and 10 others with sero-

logically proven epidemic typhus were treated with asingle oral dose of 100 mg. of doxycycline. All

patients were cured and no relapses of L.B.R.F. or

typhus occurred during the 2-week period of post-treatment observation. Each of the L.B.R.F. patientsexperienced a Jarisch-Herxheimer reaction followingtreatment, which was complicated by hypotensionand/or cardiac failure in 5 patients. This was success-

fully treated with intravenous digoxin. The difficultyof diagnosing typhus and differentiating it from entericfevers may restrict the use of single-dose doxycyclineto epidemics or to mass-treatment campaigns directedat eradicating the human reservoirs of these infections.

Introduction

ALTHOUGH a number of different drugs are effectiveagainst epidemic louse-borne typhus and relapsingfever (L.B.R.F.), most must be given in multiple dosesover a period of days to be certain of cure. Suchtreatment schedules are difficult to effect during epi-demics when medications and treatment facilities areoften limited or non-existent. An ideal drug for use inan epidemic would be one that is curative in a singleoral dose against both infections, thereby permittingrapid treatment of the population at risk. This studypresents evidence that a single dose of oral doxycycline(’Vibramycin’) cures both L.B.R.F. and epidemic ty-phus.

Methods

A total of 39 louse-infested patients with symptoms ofan acute febrile illness of short duration presenting fortreatment at the Municipality Clinic, Addis Ababa,Ethiopia, were selected for study. Patients were kept in

hospital for a minimum of 2 weeks following treatment.26 of the patients were diagnosed as being L.B.R.F. when

Borrelia recurrentis spirochætes were found in a Wright-stained smear made from their peripheral blood. Theyhad been ill for an average of 52 days (range 2-12)with high fever, severe headache, and weakness. These

patients were given orally a single tablet containing 100 mg.of doxycycline shortly after admission to the hospital.Vital signs were recorded hourly for the first 48 hoursin hospital and 6-hour thereafter. Blood-films were

examined for spirochsetes, and bacteriological cultures of

blood, urine, and stool were performed at frequent inter-vals in L.B.R.F. patients who developed fever (rectal tem-peratures above 38°C) at any time during the first 48hours in hospital.The remaining 13 patients were admitted with a pre-

sumptive diagnosis of epidemic typhus. Bacterial culturesof blood, stool, bone-marrow, and urine were obtained onadmission and again during any subsequent febrile episode.Serum was tested for Widal and Weil-Felix agglutinins.as well as for complement-fixing (c.F.) rickettsial any-

bodies on the lst and 14th day in hospital. Commercially