Tts developed from 1 month to I Yeaß

Rev. Inst. Med.

ttop.

São Paulo 2S{5) t268-27 5, setembro-ot'tubro, 1987

ßIávio Jota de PAI'rl, Lui, Sérgto AZE"yEDO, Lrr¡z Bdttl¡â¡¿! SAIÐANIIA, Lutz Est€e¡m IÁNIIEZ &

EúiI SÁBBAGA

TUBEBGULOSIS

IN

RENAL TRÂNSPIANI PÄTIENTS

Tuberculosis (TB) was diagnosed

in

25 of 466 patients \áho underwent renal tra.nsplarit over a pedod

of

15

yeârs. TB

developed

from

1 month

to

9 yeaß post-trafisplant,

_In

56% o1 the cases the onset ï¡â,S

within

the

first

posLtlans. plant yeax. TB affected seveml isolated

ot

combined orgams. putmonary invol-vement wa,¡i present

in

7670 of. caæs, eithet as isolatedr pleuro-pulmona.rJ¡ (56%)

or associated 'v/ith other sites (2OEor. _{The non-pulmonary sites Tirete: skin,} joints, tests, urinary txa,ct, c€nhâ,I nervouli syst€m and lJrmphonodul€s. The diagnosis

was confirmed by hiopsy

in

64Eo of. the cases, by identification

of

tubercle ba,. ciJli in 24Eo and only at nectopsy

in

72Eo, B'iopsy specimens cor¡Id be ctassified

in

three histological forms: exudatíve,

that

o€curred

ín

eatty onset and mote

severe cases granulornator¡s

in

late ons€t ând benign cases; ând mixed

in

inter-mediate cases- Azathiopdne doseges rwete similar aJong post-transplant time pedods

in

TB patients and

Ír

the control gtoups; and

in

Tts patients v'ho were cured arid who

died. Ihe

number of steroid trcated rèjêction cd,ses¡ was greater

in

?B t̡an

in

the control

group.

Prednisone doses wete higher and

the

¡m.

ber

of

rejection ctises was grcater

in

TB patients urho died ttran

in

those vrho

were

cured.

Fifteen patients wete curcd and ten died,

trro

of

them

of

causes

uffelated

to

TB.

Six

of

the eight TB-rela.ted deaths occurred

in

the

first

6 post-transplant months.

lhe

outcome,v¡as poor

in

patients

in

\À¡hom

TB

arose

qarly

in

post-tr.ansplaJrt _{period and u'here the exudative}

_or

_mixed

_foms

_were

present; wh€fe€.s the prog¡osis was good

in

pâtients

with

tat€ oriset and grâ. nulomatous form

of

TB-

In

one patient TB was transmitted by the allograft.

KEY

I

ORDS: Tuberculosis; _{Kiilnelr tEnsplantatlon; fnfection;}

Lmmunosuppres-sron.

SUMMAEY

fnfection

is a

frequent complication and

the maiD. oause

of

desth

in

rena;l trar¡splant patlents. This high frequenq¡ of infectioh has be,etr associated

with

immunosupp¡essive thê raw 20. Tuberculosis (TB) a'ffecting these pa-tients hâs been reported since a,s

far

bâcJI a^s

1964 28 either as isolated case retrþús

or

_as

small series 21,12. Two Ìeviews have been

þu-Eæal lTaÞsf'IB¡t Unit, ..gospit¿l das Cllric¿s" of tt¡tv€rsity of São pauto M€dicst Scl¡ool.

Âildr€ds for coll€spondero€: Dr. Fláylo Jots alê Psuls. Untdade de Tlânsplanüê Þec]âl, Eos.pitÊl atås Cl¡ric6s dâ Fscutdsdê do

Meaücj¡a a¡.4 Unlversiclstls de Seo Pardo. Av, D¡. Eìéss ats Ca¡vslho Aguis¡, 255. caixa postal 8091. CE' 0E{08 SÉ'o

São P8do. SP _- Blãsil.

IIVIRODI'CTION

blished 15,16.

_ftre

_{rcal prevâlence and the adÈ} quate managemef¡t and thetap!¡ are

still

dÞ

batable.

PATIENTS AND MEIIODS

å. retrospective analysis of 25 câses of TB

PAULil, ¡'. J. de; AZE,\IEDO, L. S.; SÀ.LD,ANH.{, !. B; LANHø, L. E. & SÂEBÀG'A, E' - Ttberculostß t[ Ëaal t¡âr,sptant patientq" Rev. I¡st. Med. troP' são P¿rro, 29t26a'275' 7947

renal transptantation over a period of 15 years

wa{i canied

out,

This is a'n incidence of 5.67¿'

Itle

minimal fouow-up period

was

2

yea$. fmmunosuppression consisted

of

.Azathioprine

2

mglkg/day and predrisone,

initially

in

tl¡e dose

of

1.5 lflgr1Kg/da'y, desreasing thereafter progressively

to

rcach 0

to

15 mg,/dây. Æ¡y

rejection crises l¡/ere treated, until the 19?4 by

0 _- 6 months

6 _- 12 months

12 _- 36 months

Over 36 r¡onths

increasing the dosage

of

oral prcdnisone ând

tåereafter by tbree

to five

courses

of

I

g

of intravenous methylprednisolcine (table 1). Six'

teen patients vtere

male.

,Ages rangÙcg from 14

to

60

years.

Ihe

tridneys used were from

living rclated donoIs

in

20 patients and from cadaver donols

ln

fi,ve.

A

control group consisted

of

25 patients. For each patient with TB we selected another patíent who had had

no

infectious complica. tions, who had u¡dergone transplantation at

the same time, had received the kidney from

the

same hDe

of

donol

(living-lelated/sada' vet), wâs

of

the same sex arld was

of

equiva' lent

age.

For this putpose tl¡e ages were di' vided

into loyeal

pe

ods.

Tt¡e statistical

analyses were based on S-tudent s

"t'test

ând "chi-squa¡e" tests,

with

5% probabiltw as the significance level.

RESIJLTS

TAALE I

Inrnu¡osupression ând post¿la¡El)lant periodE

ms/Ks/dâY 2.14 r 0.6 1.9? t 0.3?

2.12 + 0. ?6

1.97 + 0.54

the

initial

sig¡s and syrnptoms are sum' marised

in

table

II

and the sites

of

involve ment in figure

l.

I't¡.lmonary affection was

p¡e-sent

in

t4

patients (56%) eithe¡ as isolat€d pulmonary (nine cases)

or

pleuropulmonary

(five cases).

In

a furthel

five €ases

it

was

associated.

with

other

sites

of

involYement.

Thus,

the total

pulmonaÃJ¡ involvement was

16% <19 F,ølientsr.

In

six patients

TB

occur-red

in

non-pulmonary sites

only.

Chest x-râð¡

findings

in

patients

with

pulmonary involve ment are summarised

in

table

III-Tts developed

from

1 month

to

I

Yeaß post-trânsplantation.

fn

nine patienJs (367¿)

TB onset was r¡/ithin the

filst

6 months after

the

tmnsplantation. -A'

futher fouÌ

patients (20%) developed

TB

during

the

follovring 6 months. Thus

in

13 patients G6Eo) ltre onset

T,{BI.É II

Sig¡s ê¡al symptorEs ÀT the oÃset oi 1B

*in lesioú

Myalgia

R€sp. insulficie.Dcy . \tejght loss

Orcbitis

¿¡tb.l¿tgia

Meningeal tdlstion

ttrinary symptor¡s

ûE/IlE/day o.52 + 0.4I{)

p _< 0.05

0.30

+

0.09

0.34 + 0.22

p _< 0.05

0.23 10.06

18 11 7 3

2 2

2 2

2 2

1 1

I

menigoencephalic urnary fact

testicular

ø

Pulmonary 176/") osteo-arlicular

pulmonary-culaneous pulmonâry{esticular pulmonary-lymphonodular

12

;[

L2

I I 8 I I

4

cutaneous disseminated

of TB v/âs in the first

year. fn

these patients,

pulmonarf,¡ involvernent waÉt pÌesent

in

all but

number oI cases Fit. I - Sìtes of involveme¡t,

pleuro-purmoñary

PÁLLA' _{t¡anspl,¡t pationts.} F. J. de; _'AzEvÐo' L. s.; s¡uÐ,aNg.a, L. B.; rÀNEEz, L. E. & s.aBBÀGA, E. - Tube¡cìfosis in ¡eEsl

R€v. I[st. Med. trop. Sõo p¿uto, 29:268.2?5, 198?.

T"ABI,E III

CÞ€st X-I¿y fi¡dings tn cases of pulmonâry invotvement

Pulllona¡y inrütEtion only

Puldonary infilt¡atioÀ â.nd

pÌeulail lxvolvemênt

PleüÊl involvement onty

Pultno¡a¡y inftltmtio4 â¡ld

meiliartinÂl enlaryem€Et

one.

The other 12 cases Were observd u¡i_

fomly

ftom

1

to

g years after the transplaû

tation (figure

_2).

_AU

_but

_{one case}

_of

_{non_} pulrnonary _{involveÍIent occuned}

_aftex

_the

first

post.ttensplant

_{year. Ihe}

_two

_{cases of} miliary TB occurred during the

first

6 months.

N.o

l0

5 3

1

14 12

lomata were present (etr)ithelioid g¡anuloma with câseous necrcsis, giant cells aJ:d acid-fast bacilli);

(c)

mixed (three cas!es): there was a

neutrophil exudatq similBr

to

that of the exu-dative

folm,

and the

initial

formation

of

the epithelioid grânulomata

_with

_{a,cid-fa.st bacilli.} Thé exudative and the mixed forrns rsere as-sociated

_with

_a

_{worse clinical}

_picture

_and were

fou¡d

only

in

€ases where the onset of

TB

was dudng the

first

post-transptant year.

OnIy one patient tìad the g¡anulomatous _form Ìr¡Íthin the

first year.

The ¡em¿ining

six

ca,-ses occurred a,fter

the

first

posLtransplant year (figure

_3).

_{Three of the six patients rtriúr} the exudative or mixed forms dÍed, No deatfis occurred

in

patients

_{with fiìe}

granulomatous lorm.

52.6

26.3

5.26

¡'ig. 2 _- Onset or TB and post-r¡ùsplâ¡ü pê¡iods.

The diagnosis

of

TB wâs confirrned

in

16

patients (64%)

_by

_biopsy

_of

_{the a.ffeqted or_}

gan-

In

four

patients \,sho had multiple or. gan iñvolvement, biopsies ,were _{performed at} different sites.

In

six patients (2480) _{the diag_}

no,sis \¡ra¡i confirmed

by

üre identification of t¡re tubercle baÆiUi (by direct staining

or

by culture

in

specific media)

in

sputüm, urine, pleural effusion and cetebral-spina,l

flrdd.

_In

three patients TB wa"s diagnosed. only

at

nÈ

c¡opsy,

fn

13 cases the biopsied specimens could be retrospectively reasssssed. Theiy souLt be

classüied

in

tlÌree forms: (¿) exudÈtive (three cases): _{polimol*ror¡uclèar Deutrophil exudate,} disrupture of the basic tissular pattern and. nF crosis, highly _ similar

to a

common pyogenic

infection,

However, micæbiological staining

discloßed abunatrant acidjast ba.ciui bearing tlre features

of

tubercle bacilli; (b) grâ,nuloEaúous

(seven cases): üre typical tuberculous granu.

123456789

Years

1234567A

years

Fig. 3 _- Histoparhorogicât fo¡ms aDd posr _{r¡ansplant le¡ioats.}

Specific

therapy

consisted

of

_different drug combinations. fsoniazid wâs used

in

aU

patients,

The

oflret

_{drugs used were rifam.}

picin, ethambutol and sttq)tomycùr.

pâr.aml-nosâlicilic acid ând pJrrazinamide _{were seldom}

used.

T?rere \áas

a

severe rejection cdsis in

one patient

after

the

_sta

_of

the couNe of

¿hempy, which inctuated

rifampicin.

Another patient received _{thtee diffètent drug combina,} tions due

to

severe jsundice.

Of the 25 patients, 15 recove¡ed. a.fter

the-rapy.

ïhere

were no recumences. Tlte du¡a.

tion

of

the

trcetment râng€d

from 6

to

24

montås.

The

othe¡

10 patients

died.

Two deaths were r¡nrel¿ted

to

TB.

Six of the eight deaths due

to TB

occur¡ed during the

filst

6 post-transplant

_months.

_{No deaths occurred} in tJ:e nino patients in whom TB occu-rred åfter

3

years

_of

tmnsplantation,

Ihe

imnunosupptession

ùr

_TB

paüent6.

PAI'],Â, F, J. de; AZE]¡EDO, L. S.; SAI¡,ANEÂ, L. B.; L{NIIEZ, L. E. & SA-BBÅGA, E. - Tuhe¡culosis in ¡enBl

t¡aBpÞnt Ftients. Bev. I¡st. M€¡1. tto!, São P¡l¡lo, ?st2æ-275, ßA7.

doses of âzathioprine were not statisticauy dü.

ferent.

Íre

doses

of

pred¡isone were highe¡ &lthough not statisticâlly signific¿nt iD TB pa. tients than in the contlol gtoup, I?¡e number

of

rejection crises 5Ã'âs sign¡ficantly gæater in TB patients (figu¡e

_4).

A comparison

of

im-mr¡nosuppressives was made also bet!¿een TB patients who died a¡td those who were cu¡ed. There were no differences

in

telaäon

to

aza.

thioprine.

P¡ednisone doses ü'ere hlgher and

the

numbel

of

rejection clises treated rwas g¡eater

in

patients

_who

_{died than}

_in

_those who were cured (figure 5).

EI Fdrc

ø18

T]te incidence of TB in patients .with chto-nic renal failu¡e and renal transplants is higher thâ,n

that

in

the

general populationz,rs.

In

transplant patients

it

is

esti.rnated

to

be

at

0

to !-1a/o 8,75,7ß,22, ,qJthough fsvr_ studies of such câses have been published, Tts

in

renal transi plant patients is not a rare disease. LICITTENS-TEIN ând MaccREGOR 15, in _{a surve5r made} by

questionnaires received from 26 tiãnsplant

cen-tres

in

the USA,

repo

ed tlra,t 14 (57-7Eot of. them had had at leâst one case

of

TB during the lâ'st 10

yeâË.

One of the cent¡es reported

22 cases. Itley estim¿ted that the incidence of

Tts among tmnsplant patients ryould be 313-340/100,000 per year (0.31

to

0.347¿).

rhis

is approximately 24 times greater than the inci-dence

in

the geri€ral population

_of

the USÅ.

In

ou¡

present stud¡¡

(of

Braziliari patients

only)

the incidence

of 1B

was

5.67".

This,

extremell¡ high frequencõ¡

oI

TB

could be ex,

plained by tile high ptevalence of TB in Bmzil, which

is

esttmated

to

be

at

0.5%

oÍ

lhe

ge-neral populãtion ó.

Immurosuppression

is

by

far

the

main predisposing fa.stor

to

infection

in

t¡ansplant

patients,

Which drug

is

mainly ¡esponsible and t}le exact mechanidm of this predisposition

is not

yet

deiined

æ.

Âzathioprine, as

it

is well ¡mown, impairs the .host defence mecha.

nisrns against infection 20. However, ¡we _for¡nd that there rwâs _{not.a significant difference} bet-ween the doses of azathiopdne administered to Tts patients and

to

the cont¡ol group as well

as

to

TB

_{patients 'who lwere} cured and to

those ,s'ho alied, although slightly higher in the

latter.

By contrâst, we found that TB patients

receiÌved more steroid treatmenf

for

rejection than did the control

group.

Oral prednisone doses u'ere considerably higher and the

num-ber of

rejectiolr srises treated were greÐtet

in

TB patients who died a,s comþâred

to

tho-se who,were

q¡red.

TB patients received

mo-re

oral prsdnisone th¿n

did

sontrol patients

(althowh not statistically

significant).

These

findings stress the

lole

of

corticosteroids as

a

prcdiq)osing faÆtor

ùr

developing

TB

in

transplant pBtients, as weU aß incr€asing the mortali{y ¡ate

in

these

pattents.

Ttre main

role

of

cofücosteroids

i¡r

predlsposing infeG tions

in

generâI, and

TB

in

Þafticr¡lâr,

is

a disputed subject 5'8'18Ð'æ,s1.

Ma¡l!¡

autho$

propos€ the use ,of

a

louti[ely

low

dose

ol

27r Fig. 4 _{- IrnmuosuÞpresion rn TB ùd} jn cont¡ol g.oup,

d@a

dè^bs Zt

DISCUSSION

n ot r€l.crront

ñE/kvdãv

Fig- 5 _- Irr¡mmosuppression iû TB patienrs _{who died} snd

Serum creatüúne levels were

not

stetisti-ca¡lj¡ different

in

TB

patients as

in

the con

trol

group.

One petlent developed

TB

in

the urin¿ry

tract ând

in

tJIe lungs.

Ât

the same time tu. bercle baculi wâs identified

in

tf¡e urino of the donor (her mother).

Two patients received isoniazid

propþlao

tically started sooB aft€r the transplentation. Tlds proved ineffectl"e

in

prcÍentlng TB reæ tivatÍon.

¡ or reþdi6n.

PAUII\, F. J. de; AZEVEDO, L. S.; SAIÐÀNH-A, L. B.; IANHEZ, L. E. & SA.BBAGÄ, E. - Tulrercutosis in rcnål tmnsprant p¿tients. Eev. IDst. Me.l. úr.op. Sño P¿uIo, Wt2æ-2l5,

lS87-co¡ticosteroids

to

avoid side effects, the main one

bqi¡g

inJection

20.

LICHTENSTEIN afld

MaCGREGOR 6; in theif review of TB in trans-plant p¿tients, found that the mean dJosage of

prednisone

_{in TB}

pâtients q¡as 342 mg daily (¡ange _{of 10 to 80 mg).}

_Ihis

_{can be considercd} a moderate to high dose of steroids. The ave. ra'ge dose of azathioprine \¡ras 117 mg daily (a considerably low dose) afid only four petients wele receiving more than 150 Ing

daily.

So-me authors, however, did

not

implicate corti-costeroids as the main factor

in

predisposing TB infection

in

¿ransplant patients s'8,2e.

T?re onset

of

TB

in

the majotih¡

of

ouÎ Þatients (567¿) occurr€d dudng the

first

post-transplarìt ye¿r¡ _{a period in which steroids axe}

used

in

greater dos€s and when alrnost a

rejection clises occut (table

_I).

The dosage

of

azathiop ne wa^s constant through.out the years (table

I).

The remaining 44Ea o1. cases

developed unifofmly

duing

t}re following

_I

yeãrs. ï.1]e cases \,yhich occr¡¡red early

in

the post-transplant period tended

to

be mote

se-rious ar¡d

to

have pooret prognosis,

with

a

high mortality

tate.

The

two

miliarj¡ cases

occured

!'¡ithin the

first 6

posLtÈnspla¡¡t

months.

By contrast, the câses

in

which TB arose

later

tended

to

be mild

and \áith a

good prognosis.

In

the cases ÍeÞorted

in

ttre

literature, there \ras a wide range

in

the tjme

of

onset

of

TB.

LICI]Irm{STEIN and Mac

GR,EC.OR t5 stat€d

that

64íy'o of.

ttre

cases occurled rwithin tl:e

first

post-traÐspla.Dt year. The onset ranged

ftom

I

to

78 months.

The supposition

that

the rwell-know-n

im-munosuppressiye effect

of

u¡aêmia could be

present aftef a Successful renal transplant ar¡d

thus predispostng _to inJections 8¡r _{is arr}

attracti-ve

h¡r¡lothesis which

cafl

not be

ruled out, Ifowever, this hylpothesis bas not b€en proved a¡d ha"s even been rejected 10,2, Altlrough wê could suspect that patients _who had had mote rejection crises had

a

wotse rcnal fi¡Ì¡ction, and thus ân impaircd immwlity, sen¡m cre¿-tinine levels were not significan

y

different as

between TB and control patients.

One point

of

great int€rest qras _{the fact} that

TB

appeared under thrce diffe¡ent histo-logicâl pictures: exudative, granulomatous and

mlxed.

T'ire exudãtive

foÎm

wâs pEsent in the

first

montlß afid was associated ,with a

bâd clinical picture and lwith a _{'worse pÌogno.}

sis,

Grånulomatous TB had a clinical picture

similar

to

that found

in

non-Ínmunosuppres

sed patients, wa,s p¡esent mostbr aftet the

first

post-transplent year and had

a

good ptogno-sis. The mixed form had aspects of both forms, lying

"in

bet\Ã'een". We might speculate that coúicostercids in high doses could be the main factor

in

inducing the atrÞearance

of

the

exu-dative and mixed forms (mtheJ than the gra. nulomatous one)

in

some o¡ ouÎ patients du.

ri¡g

the early poshtransplant period.

The initial signs end sj¡mptoms of TB can be mild, undefined and poh¡morphic.

Itle

pa. tient caÌ! deteriotate rapidly

if

TB is undiagnG.

sed

or

diagnosed too

late.

I?ris

is

more

evi-dent during

the

first

post-transplant months.

T'hese facts are corÌoborated by the high mor-¿ality râte artd

by

the fåct that three

of

ouf

patients had theif diagnosis of TB €stablished only

at

nesropsy, ï'l-resq findings were also observed by others 18,19,2a. Tlrus the est¿blish.

ment

of

eady diagnosirs and immediate insti-tútion of tf¡er¿py

is of

the utmost importance

tur affecting tåe prognosis. TB should be sus-pected in an iU-d€fined febrile conditions

affec-ting ha¡rsplant patients, and even more when lungs are affected,

All

attempts

to

establish the diagnosis should be made 16,18,26. T1re p¡€"

sence

of

tubercle baqilli should

be

searched

for

on airways secretions, udne

ot

suspegted

secretions, either by direct staintng

or

by cul. ture

in

spesific media. âs aÆid-fast bacil¡i are

not

frequently found and cultures may take weeks

to

be positive,

_a

more aggressive aÞ proach, such

as

bronchoscol¡¡

or

bioÞsy of

the

affected orgar¡,

is

s¿Ivisable. Open lufig biopsy should be considered when unexplained pulmonâry infiltrate

is

present 4,1€,26"

It

_was perlormed

in

10

of

our patients, had no

com-plications and

led

to

positive resu¡ts

in

all eases.

In

t}le presence of a suspected infected paiient,

if

TB cannot quickly be confirmed, a specific "btind" thempeutic trial should be ins"

tituted.

This

ca[

be life-saving.

Extrâ

puLnonary

TB

occu.rred

ill

12 of

our

pauents. sorne

of

then

v¡ith

multiple organ involvement. Two of t¡em had miüary dissemlnatiorr

l'his

hâs been frequently cited in the literature 3,48 )2,13,16,1ß,181s 2122,21,26 2Å. Thø

disseniDated forIn \rras

fouid to

he

at

43.5qo

of

23 ceses collected by LICIIrENSTEIN and

P¡IIIIA, ¡. J. de; ÅZEYEDO, I. S.; S,AIJ)ÁNHÁ, L. B.; L{NIÍEZ, L. E. & SABBAGA, E. - îrbe¡culosis in rcnâl

tlansp¡åÃt patients. _n v, InEt. Med. iro!. Þ¡io P¿u¡o, :9:268-2?5, 198?.

Specific therapeutic regimen varies $'idely 34,8)2,75,16,t81921,2224,26 _{af¡d depends on tfre}

¡ê

nal function and on the presence

of

liver dar

mage. There

is

no agreement on how many and which drugs shou.trd be used, and on the duration of tf¡e treatment,

It

is reasonable to suggest that thrce drugs should be used and

the treatment should take one year

at

least.

Some authors propose longer t}lerapy, even 3 years s'3r, The mâ'in point rests on the choice

of drugs. Hepatotoxicib¡ can be a serious side

effect of TB treatment 16'21, _{T¡ansplarit patients} may have hepatopathy and azathioprine and

syclosporin can be hepatotoxic æ. Thus isonia¡

zid,

rifampicin and pyftøinamide should be

used with caution. One of our patients

deve-loped jaundice after the start of TB treatment;

the

drug combination was changed three ti-mes

in

order

to

minimise the

liver

daÌnage.

This

approa.ch wa,s unsucessful and

tfle

pa-tient eventually died

of

liver insufficiency. Rifampicin poses

a

sp€cial

_þroblem.

It

can interact

with

micrósomes

of

hepatocytes

enhancing stercids catabolism 11'17 _{a.nd thus}

predisposing

to

rcjection-

This occurred in

one of our patients. Mo.A.LLISTER et

alr

found

a

4570 increase

in

tÀe plasma cleatance of prednisolone and

a

reduc€d amount

of

drug aveilability

to

tissues

by

66%

in

patþnts

rê

ceiving

rifampicin.

Thus

oral

doses

of

ste. roÍds should be inereâsed

duing

therapj¡ vrith

dfampicin.

Rifampicin also increâses tJ|e ca" tabolism of syclosporin, probably by activation

of

hepatic enzymes 7'14. Increased oral doses

of

c¡¡clûspodn were not folldwed by a

corres-ponding increase

in

cyclosporin blood levels,

and did not prcvent rejection cris€s

in

cases repoÌted

in

tl:e Utemture 1,9ii,4,23.

It

_{has been}

suggested

either

that

rifampicin shouJd be

avoided in cyclosporin-treated patier¡ts 1,23 _using

pylazinamlde instead

e;

or

that

azathtoprine

should be used inste&¿l

of

cyclosporin

in

pa-tients who must receive rifampicin

I,

Tt¡ere-lore

it

seems that cÌyclosporin and rifampicin should not be used concomitantly, but

if

this drug combination must b€ necessary, the dos€ of cyclosporin should be increased a6 much ar¡

is

needed

to

reach therapeutic c5¡closporin blood levels.

The use of isoniazid a.s a p¡oprhylâctic agent

has been proposd

for

patients

ln

these con"

ditions:

coming

from

endemio

TB

environ-ments, with known family contaÆts,

with

sus-pected caJcified lung lesions, having had pr+ viously inadequately treated

TB

or

receiving

a

kid¡ey

from

positive tuberculin tÆsted

do-nor 1,16,18,19,ã.:ì{J. _This policy

is

a

_{subject of} concern. fsoniazid can induce neuropathl¡ in

patients with renal impairment and

it

ca.n be

hepatotoxic. Moreover,

in

transplant patients in whom chronic hepatopathy may be present,

and who are expected

to

receive azathioprine and/or cyclosporin, two potentially hepatotoxio

drugs æ,æ. T?ìe efficacy

of

isoniauid âs a pre

phyl¿ctic agent

in

transplarìt patients has not

been provedæ, Two of our patients developed

TB

despite having received prophylactic

iso-niazid,

This was also the ca.se

in

three

pa-tients reportqd bsr SAIIN and LAI<SHMIN.á.-RAYAN Ð _{who receÍved}

co

_icosteroids (one _for

renal trar¡splant and

two

for

other reasons)

and prophylactis

isoniazid.

,Although

TB

is highly prevalent

in

Bmzil

it

is

not our policy to presqibe isoniazid as a routine propllJ¡lactic

cfrug.

TB

in

transplant patients is believed to be

an exacerbation

of

previous and quiescent

fo-ci,3r.

Hdwgver,

it

is possible that the sedous

Iìulmona'ry or disseminated TB seen during the first months of the posltrar¡splant pedod could arise

from

p

me inJection. Transmission of

TB

from ¿ contaminated dono.r

via

the graJt

has been described 13,15,å1,25.

It

_{ïra.s the case}

of

one

of

our patients who dev€loped udnâry

tÞct

and pulrnonary

TB

a

few

months afte¡ receiving the allograft. Itrinery tract TB ráas diagnosed also

in

the

donor.

Retrospectively,

it

rwas found that

at

the time

of

transplanta. tion the donor had a

mild

and neglested

leu-Íocytuda.

In

conclusion,

TB

in

renal transplant pa,

tients

is

e

serious medical complication. Its

lrequency

is

10

to

20 times greater than that found

in

the

genelal

population.

Morbidity and mortality ale higher during the

first

mon ths after the trånspla¡tation, This coincided in ou¡ series with occurrence

of

exudative and

mixed

forms.

Corticosteroids

in

high

doses

are p¡obably important facto¡s in predisposing the patient to TB and

in

incrcasing morbidity and

mortalitl¡. TB

can

be

transmitted via the dono¡ kid¡ey.

RESIJMO

PÄUL,A, F. J. ate; AZE\¡EDO, !. S.; S4¡iDA¡EIÄ, L. B.; IÁNI{EZ, L. E. & SABEÀGA, E. - Tì¡berculosis iû r€I¡Âl Eanspla.nt pÊ¿ients. Rev. I¡st. Med. t¡op. São pauto, t9:26&2?S, tg8?.

Tuberculose

(TB)

foi

diragnosticada em 25 de 466 pacientes submetidos

a

transplante

te-nal.

A TB surgiu entre

I

mês e

I

anos pós,

transplante- O puLnão

foi

aßometido em 76Eo

dos câsos, isolsdamente G6Eo),

ou

associado

a outras localizaçóes (2OEo). Os out¡os órgãos

envolvidos for¿m: pele, aÍiculações, testículos,

trato

urinário, sistema nervoso central

e

lin-fonodos.

O

diagnóstico

foi

confirmado por biópsia em 64% dos ca.sos, pela, identificação

do

bacilo em 24Vo

e

apenas

à

necrópsia em

LzEo, TTês formas histológisas foram identifi-cadas: exudåtiva (nos casos de aparecimento precoce e de maiot gravidade) gTafiulomatos¿

(naqueles benignos e de a¡ratecimento tardio)

e

mista (naqueles

intemediários).

,{s doses de azatioprina foram const¿ntes a,o longo do

perÍodo pó,s-hansplante, _{tanto no grupo}

tuber-cu.loso como no controle, bem como nos pa.

cientes tuberculosos que falecemm

e

que se curaram. O núme¡o de crises de rejeiçã,o tra¡ tadas foi maior no gtupo TB do que no grupo contlole. .4.s doses de ptednisonå e o nrimero de ctises de rejeiçáo foram maiores nos pa.

cientes tuberculosos que falecetam do que

na-queles que _{sobreviveram. euinze pacientes se} curaÎam

e

10 faleceram, oito de gausas fela. cionadas à

TB,

Seis destes óbitos ocol'rerâln nos

6

primeitos meses pós-hansplante.

_tm

um paciente a TB foi hansmitidâ pelo enxerto.

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I¡ecebtdo pÀle publicåção eû 0?/2/1986.