cystitis. Group 2?Unilateral renal tuberculosis. Major lesion necessi- tating nephrectomy ; cystitis. Group 3?Bilateral renal tuberculosis. Nephrectomy for the.
Edinburgh
Medical
Journal
December 1952 the chemotherapy of urinary tuberculosis By WM. G. I.WIMSETT, L.R.C.P., L.R.C.S.I. Robroyston Hospital, Glasgow
At Robroyston Hospital, in December 1948,
a controlled trial was for tuberculous disease of the urinary therapy tract. This investigation, conducted under the auspices of the Tuberculosis Research Unit of the Medical Research Council, was concluded in December 1951. At the completion of the trial 137 patients had been
instituted
of streptomycin
studied.
Selection of the
for
streptomycin treatment was made kept at the M.R.C. offices. Streptostatistically prepared to mycin has been given 70 patients and 67 were selected as control
from
cases
list
a
cases.
patients were grouped into five categories :? Group 1?Unilateral renal tuberculosis. Minor lesion cystitis. Group 2?Unilateral renal tuberculosis. Major lesion tating nephrectomy ; cystitis. Group 3?Bilateral renal tuberculosis. Nephrectomy
The
more
without necessifor the
advanced lesion. in
the
remaining kidney subsequent to nephrectomy for unilateral disease. Group 5?(a) Major bilateral tuberculous lesions ;
Group 4?Tuberculosis occurring (b)
Minor bilateral tuberculous lesions.
Complete urological investigation was carried out on all patients whether treated by streptomycin or not. The investigation was repeated after treatment and thereafter the patients were observed and reassessed at intervals of three months. Tests for streptomycin resistance and assays of streptomycin levels were performed routinely. Observation ?n
toxic effects with
also made. 1 he
particular
reference
to
vestibular
damage
were
treated
by streptomycin were given one gramme intramuscular injections for ninety days. Controls gm_ and treated streptomycin patients received similar general medical patients
daily in two ^atment. Read
0spital, V?L.
at a on
Meeting
of the Tuberculosis
Society
of Scotland held at
Bangour
25th January 1952.
LIX. NO.
12
573
2 N
WM. G. WIMSETT
574
In March 1950 a preliminary report was presented by Jacobs and Borthwick to the section of Urology of the Royal Society of Medicine. This report was based on the study of 90 patients. Streptomycin had been given to 46 and 44 had been used as controls. At the completion of the trial a further 47 patients had been studied. Analysis of the additional cases confirms the conclusions reached in the preliminary
report.
Broadly
these conclusions
established
were
:?The treatment has
no
effect
on
lesion.
By some process encouraging constriction there is a possibility that the focus, though itself remaining active, may become shut off. A regression of the constriction, however, can occur. Streptomycin therefore cannot be recommended to supplant an
caseocavernous
surgery, and in clinical unilateral renal tuberculosis the diseased kidney should be removed, or, where possible, partial nephrectomy should be
attempted. Its automatic employment in cases unsuitable for surgery is not advised. Thus, when there is an advanced bilateral renal lesion or an advanced lesion in a solitary kidney, no improvement in the kidney lesion can be anticipated, and vesical contracture may be accelerated where In
cystitis Group
was
2
previously
present. cases for
cases, that is
nephrectomy, cystitis, strepto-
mycin may prove beneficial as an additional measure possibly before In addition, it should afford some measure as well as after surgery. of protection against activation and development of the disease in the
apparently healthy kidney. This statement is given with reservation, however, for at the completion of the trial, in Group I cases, the contralateral kidney became tubercle positive in 3 out of 10 treated cases, whilst this occurred in only 3 out of 11 controls. Streptomycin does have a beneficial effect on secondary tuberculous cystitis, but this would appear to be relative to the presence and degree of disease in the upper urinary tract. Thus in Group 2 cases, that is those with a unilateral renal lesion in whom the affected kidney has been removed, cystitis has cleared and the urine has become tubercle negative in an appreciably larger number of streptomycin treated cases than has occurred with controls. In Group 5 cases, however, consisting chiefly of patients with well-established bilateral disease, no beneficial effect" on the bladder resulted. In the few cases in whom the bilateral lesions were minimal, the effect of streptomycin on the bladder has been
good. Toxicity.?As previously stated, particular attention has been directed towards the occurrence of vestibular damage. For each case, whether receiving streptomycin treatment or control, routine vestibular function tests were performed before and at the completion of treatment.
were carried out under the direction of Dr throat consultant to the hospital. Comand McKinlay, ear, are not yet available, but the follow results obtained of the details
The examinations
John plete ing observations
nose
can
be made
:
THE CHEMOTHERAPY OF URINARY TUBERCULOSIS
575
The incidence of vestibular
damage in streptomycin treated cases number of patients the damage was slight, having been detected only after routine tests. In a small proportion of cases the disturbance was marked, and in one such case cochlear damage, giving rise to deafness, occurred. Both the vestibular and cochlear damage
Was
In
high.
a
Were irreversible.
Combined Streptomycin and P.A.S. Therapy.?The effects of combining streptomycin with P.A.S. were investigated in 20 patients, 5 of whom had been previously treated by streptomycin. The remainder, r5 in all, had received general medical treatment without streptomycin. In each case the previous treatment had been given under the conditions of the M.R.C. trial, and at the completion of the streptomycin ?r control period in every case further treatment was required. On admission to the original trial, the cases had been classified in groups in the following proportions :?
Group 1?Three streptomycin Group 2?Six control cases. Group 3?Two streptomycin ;
;
four controls ; total
seven.
three controls ; total five.
1 he two remaining cases, both controls, were classified as Group 5. For the purposes of this investigation the results of the initial treatment in each group are compared with that of combined therapy. In each case streptomycin, 1 gm. daily intramuscularly in a single dose,
ninety days with P.A.S. 15 gm. daily in divided doses. 1.?The 3 patients after treatment by streptomycin, remained tubercle positive. In one the pyelographic appearances of the affected had improved. After observation for a period of eight months, Xvas
given
for
Group
kidney
the
two in which no change had occurred developed cystitis and involvement of the other kidney. In one the original lesion had worsened. Following combined therapy the first case showed further pyelo-
the urine became negative for tubercle bacilli, and had remained thus for a period of six months. Of the two cases which had deteriorated, the cystitis had improved in both ; in one the
graphy improvement,
c?ntralateral kidney had become tubercle negative, and the affected
kidney
Three months later the urine was tubercle removed. the remaining kidney normal and no cystitis was present, this having been maintained for twelve months. In the third case the c?ntralateral kidney remained involved and further worsening of the was
negative,
?riginal
renal lesion had taken
place. above, following combined therapy, one case showed further improvement which has been maintained for six Months. In another the bladder and contralateral kidney were 3rnproved and surgery for the original lesion resulted in improvement,
Summary.?In
has ^hich lsease
the
been maintained for twelve months. arrested in the last case.
The
course
of the
was not
Control ?ne
had
Cases.?Of the 4 cases, all remained tubercle positive, developed cystitis and the remainder involvement of the other
WM.
576
kidney.
In
minor lesion
one
of the
developed
G. WIMSETT
latter, the original lesion had worsened and in the contralateral kidney. TABLE
Group
i
Urine
Total.
Streptomycin
Conversion.
Cases
a
I
After
8 Months'' Observation
Cystitis Developed.
Pyelographic Changes.
Involvement of Other
Kidney. W.
After
S. and P.A.S. Other
Cystitis. Total.
Urine
None.
Imp.
I.
=
!
Kidney. J
Pyelographic Changes.
1
Conversion.
Improved;
W.
=
Worsened;
U.
=
u.
Unchanged;
N.S.
N.S.
=
W.
No
spread.
therapy, three were tubercle negative. Of these one pyelographic improvement but has failed to return for followThe others showed no pyelographic improvement examination.
After combined showed up
TABLE
Group
I
Control Cases at the
II
Completion of 3-6
Months' Control Period Pvelographic
Total.
Urine
Conversion.
Cystitis Developed.
After
Urine
Involvement of Other
and
=
Improved
; W.
=
Worsened
None.
partial nephrectomy
version in both
cases
was
;
U.
Pyelographic
Kidney.
Conversion. Imp.
I.
Kidney.
S. and P.A.S. Cystitis.
Total.
Changes.
Involvement of Other
=
U.
Unchanged
undertaken.
has been maintained for
;
Changes.
N.S.
N.S.
=
W.
No
spread.
Thereafter urine con" over
six months.
The
THE CHEMOTHERAPY OF URINARY TUBERCULOSIS
fourth
case, which remained tubercle
pyelographic
577
had shown bilateral
positive, period.
the control
lesions
following Summary.?Of 4 cases, urine conversion was attained in three, pyelographic improvement in one, no change occurred in the last case. Group 2.?Of the 6 patients in this group all remained tubercle positive following a control period. No improvement in the degree of cystitis was noted and in two involvement of the other kidney had occurred. After combined therapy all became tubercle negative pletion of treatment, the cystitis had improved in every involvement of the other kidney was detected. TABLE
Group
2
Control Cases at the
Completion of 3-6
After S.
no
Involvement of Other Kidney.
Worsened.
Unchanged
a?id P.A.S. Cystitis.
Total.
com-
and
Months' Control Period
Urine Conversion.
Improved.
the
III
Cystitis. Total
at
case
Involvement of Other Kidney.
Urine Conversion.
Improved.
Worsened.
Unchanged.
occurred in all cases and is the present, a period varying from two months in the last case to fourteen months in the earliest case. Group 3.?Of the 5 cases in this group, two had been treated by streptomycin, but both remained tubercle positive after treatment. In ?ne the remaining kidney was improved but no improvement in the Uegree of cystitis resulted. In both, bladder contracture had commenced.
Summary.?Marked improvement
Maintained
to
After combined therapy the lesions of the remaining kidney in both
Cases
were improved. One became tubercle negative, the other remained ^bercle positive until the sixth month after treatment. The urine
conversion has been maintained in both for he
degree
ladder
of
cystitis
was
difficult
a
to assess as a
further six months, result of increasing
contracture.
renal lesions in both cases were improved, urine occurred at the completion of treatment in one case and in e ?ther on the sixth month after treatment. Controls.?Three cases all remained tubercle positive, no change as observed in the degree of cystitis and the lesion of the
Summary.?The
conversion
ney had worsened in
remaining
one case. 2 N 2
WM. G. WIMSETT
578
After combined therapy three were tubercle negative, the degree of and the disease of the remaining kidney were improved in each case. At subsequent examination, after twelve months, one had become tubercle positive and deterioration of the renal lesion had occurred.
cystitis
TABLE IV
Group 3 Streptomycin Cases
at
Co?npletion of
Treatment
Urine Conversion.
Other
Cystitis Unchanged
Total. Bladder.
Kidney.
Improved.
After Urine
Unchanged.
S. and P.A.S.
Conversion.
Other
Cystitis Unchanged.
Total. Bladder.
Kidney.
Kidney.
Kidney.
Improved.
Unchanged.
A second case has remained tubercle negative for fourteen months, but the filling defect in the affected kidney has reappeared. Repeated In cultures of urine, however, have failed to show tubercle bacilli. disease was detected obvious in no the case third the remaining kidneyTABLE V
Group 3 Control Cases at
Completion of Control Period
Urine Conversion.
Cystitis.
Other
Kidney.
Total. Bladder.
Kidney.
W.
U
U.
W.
After S. and P.A.S. Urine Conversion.
Cystitis.
Other
Kidney.
Total.
Kidney.
Bladder.
The urine remained tubercle
negative
but
progressive bladder conAt operation a specifound to be free from tubercle
tracture necessitated uretero-colic anastomosis. men
of the
bacilli.
kidney urine was
obtained and
THE CHEMOTHERAPY OF URINARY TUBERCULOSIS
Summary.?Three
after treatment
cases
were
improved,
579
urine
conversion was maintained in one for twelve months. The other two remain tubercle negative to the present, a period of fourteen months and six months. Group 5.?Two patients were selected for this group, in one of advanced. After the control period both cases positive, in neither had the cystitis improved nor had pyelographic changes occurred. After combined therapy one case was tubercle negative, the cystitis had improved but no pyelographic improvement was noted. This has been maintained for six months. In the other case the advanced bilateral lesions remained unchanged and rapidly progressive bladder contracture took place.
whom the disease
was
remained tubercle
TABLE VI
Group 5 Control Cases
at
Completion of Control Cystitis.
Total.
Pyelographic Changes?N one.
Urine Conversion.
After
S. and P.A.S. Cystitis.
Total.
I
no
=
Pyelographic
Urine Conversion.
Improved;
W
Period
Changes?None.
Worsened;
U
=
Unchanged.
the worse showed Summary.?Two bilateral cases were treated ; tubercle negative and has improvement, the less severe became
remained
so
for the past six months.
Conclusions
The results obtained, following treatment by combined therap\ the patients in this series, cannot be strictly compared with those of the treated cases. Of the 20 patients treated, 5 of these
had
streptomycin
1 received streptomycin at an earlier date, the remaining 5 general Medical treatment. However, with this imperfect basis for comparison, As in the case the case for combined therapy appears slightly better. ?f lesion caseocavernous responds poorly streptomycin the established to urine combined however, therapy, treatment. In 5 cases treated by
conversion
was
attained, in
2 cases
partial nephrectomy
was
performed
WM.
580
G. WIMSETT
this tubercle negative phase and the conversion has been maintained for six months. In one the lesion in the solitary remaining kidney The urine in this case was rendered free from was well established. tubercle bacilli for a period of twelve months. In the remaining 2 cases
during
the lesions became shut off. In one of these it has remained thus for six months, in the other the constriction has regressed after fourteen months but the urine remains tubercle negative. Combined therapy appears to afford a greater degree of protection the contralateral kidney than does streptomycin. In all cases in which spread to the other kidney was displayed by the presence of a to
tubercle
positive urine, without an obvious pyelographic lesion, urine conversion was attained. In other respeets the results obtained were similar to those of the streptomycin treated cases. It should be borne in mind, however, that every case, in both the M.R.C. trial and in the above group, received general sanatorium treatment and, where indicated,
an
streptomycin sanatorium
operation nor
was
combined
performed. therapy is
It follows then, that neither alternative to prolonged
an
surgery where conditions are favourable. carried out a follow-up of patients operated upon for renal tuberculosis at the hospitals of Stockholm from 1934 to 1943. The results have yet to be presented in detail, but Ljunggren considers that the endeavour to improve the results of treatment by early diagnosis and early operation has not met with the success which was anticipated. He suggests that early diagnosis should be followed care or
Ljunggren
by
has
to
recently
strict sanatorium treatment,
is in
a
more
quiescent phase,
As to the
choice
of of
chemotherapy
and when the disease
surgery.
chemotherapeutic agent, Ljunggren
has
using P.A.S. alone for prolonged periods. Lloyd, Baumrucker and Stonington (1948) consider that streptomycin by itself has a very limited value and is not curative where there is a positive pyelogram. In early tuberculosis, however, where the pyelogram is negative, it is considered to be of great attained
some measure
success
benefit. Lattimer et al. (1948) using streptomycin 1 -8 gm. daily for 120 days obtained a good response in early renal lesions, but where the renal disease, as shown by pyelography, is marked, the author considers that nephrectomy should be performed.
In my opinion it is not unreasonable to expect an enhanced result from a combination of both drugs. The small series of patients treated in Robroyston Hospital in this fashion offers some evidence in support of this. Ross
(1951) has reported in a review of 51 cases the effect of (1) streptomycin ; (2) streptomycin and P.A.S. ; (3) streptomycin and P.A.S. alternatively ; (4) streptomycin, P.A.S. and thioparamizoneIn this series the best results were attained using methods (3) and (4). Lane (1951) has reported a series of 52 cases, 9 of whom received streptomycin and moogral, the remainder streptomycin and potassiumet
al.
THE CHEMOTHERAPY OF URINARY TUBERCULOSIS
iodide.
The latter
581
believed to promote solution and absorption of material exposing masked tubercle bacilli to the influence of the streptomycin. A 48 per cent, conversion rate is claimed. Streptomycin and potassium iodide is considered the most promising combination. The most marked success was attained in those patients in is
caseous
whom the urine from the solitary remaining kidney contained tubercle bacilli, but in whom no obvious renal lesion was demonstrated. This type of case has also responded well to streptomycin alone, and to streptomycin and P.A.S. as reported above. It may, however, be of some significance that the cases treated by Lane, in the above series, Were not
In
subjected
noted.
In
reverted
to
sanatorium regimen. patients treated, calcification of the kidney was of these was urine conversion attained, this patient
to
of the 52
11
only one positive
after
one
presence of calcification,
year.
even
to
a
The author concludes that in the minimal extent, success is most
unlikely. Lane has also
reported
the
success
of bladder instillations in the
treatment of patients in whom tuberculous cystitis has persisted after The substance used is designated B. 53. It is a soap derived from a branched fatty acid used in 0-5 per cent, water solution buffered to^H 7-2. In patients with cystitis and spread to the remaining
nephrectomy.
kidney,
local treatment proved unsuccessful. preliminary report on B. 283 is included. This drug, a phenazine dYe, was given orally to 8 patients. An immediate conversion rate of 5o per cent is reported, but in half of these relapse occurred, leaving a A
conversion rate of 25 per cent, at the time of the report. In this brief communication the work performed at Robroyston has been detailed, and reference has been made to the conclusions of other workers. By many the chemotherapy of renal tuber-
hospital
culosis may be condemned by the multiplicity and diverse combinations ?f drugs employed. The variety of reagents subjected to investigation is, however, an index of the increasing ambition on the part of both
SUrgeon
and tuberculosis
tuberculosis.
physician
to
solve the
problem
of renal
positive value in the treatdegree of protection to tuberculosis, early ^-he contralateral bladder in secondary the to and kidney, improve tuberculous cystitis following nephrectomy- In addition, though the incidence of post-operative dissemination in renal tuberculosis is low, :t *s significant that no such occurrence has been reported in patients receiving chemotherapy. It is becoming increasingly obvious that the majority of workers in this field are discarding the doctrine of immediate nephrectomy ?r renal tuberculosis. From the time of diagnosis the patient ?uld receive sanatorium treatment, under the supervision of a tuberculosis physician, the latter working as an integral part of a
Chemotherapy
ment of
^logical
has been shown
renal
team.
to
to
have
offer
some
WM.
582
G. WIMSETT.
REFERENCES "
JACOBS and Borthwick, (1950), Streptomycin in Urinary Tuberculosis," Proceedings of the Royal Society of Medicine (June), Vol. XLIII, No. 6, pp. 453-466 (section of Urology, pp. 19-32). The Treatment of Lloyd, F., Baumrucker, G. and Stonington, O. (1948), Urinary and Genital Tuberculosis with Streptomycin," Surgical. Clin. N.A. (December), pp. 1639-42. Lattimer, J. K. et al. (1948), Streptomycin Treatment of Genito-Urinary Tuberculosis." Tuberculosis Joum. Ur. (December), 60, 974-85. LjUNGGREN, Communication. Lane, T. J. D. (1951), Chemotherapy in Urinary Tuberculosis," Irish Joum. "
"
"
of M.S. (September), 309, 393-405. ROSS, J. C. et al. (1951), "The Bacteriostatic Effects of the Newer Drugs in the Treatment of Genito-Urinary Tuberculosis," Lancet (May), 1, 1033-36.
