Marco Aurélio Silva Lipay, Irene de Lourdes Noronha Armando Vidonho Júnior, João Egídio Romão Júnior João Carlos Campagnari, Miguel Srougi
Lymphoce le : a possible re lationship with acute
ce llular re je ction in kidne y transplantation
Urology and Nephrology Clinic, Beneficência Portuguesa Hospital, São Paulo, Brazil
INTRODUCTION
The incidence o f lympho cele a fter rena l transplantatio n varies between 0 .6 and 1 8 % o f cases,1 ,2 and many facto rs have been asso ciated to its etio lo g y. Amo ng these facto rs, iliac fo ssa preparatio n, kidney bio psy, diuretics and the use o f c o rtic o ste ro id s in hig h d o se s sho uld b e mentio ned.3 ,4
Cellular rejectio n o f the kidney allo g raft has been described as a po ssible causal facto r o f lympho cele.5 This immuno lo g ical pheno meno n leads to an intense lo cal inflammato ry pro cess and an increase in reg io nal lymph flo w.5 ,6
The present study analyz ed the po ssible a sso c ia tio n b e tw e e n lymp ho c e le a nd a c ute cellular rejectio n 1 7 0 kidney transplantatio ns.
METHODS
O ne hundred a nd seventy pa tients, (9 0 ma le a nd 6 0 fe ma le ) sub mitte d to re na l tra nsp la nta tio n b e tw e e n M a rc h 1 9 9 2 a nd January 1 9 9 7 were studied retro spectively in the Uro lo g y and N ephro lo g y Clinic o f Beneficência Po rtug uesa Ho spital.
The surg ic a l te c hniq ue use d fo r kidne y transplantatio n was the retro perito neal appro ach
ABSTRACT
CON TEX T: The incidence o f lympho cele after renal transplantatio n varies between 0 .6 and 1 8 % o f cases,and many facto rs have been asso ciated to its etio lo g y. Cellular rejectio n o f the kidney allo g raft has been described as a po ssible causal facto r o f lympho cele.
OBJECTIVE: To analyz e the po ssible relatio nship between lympho cele and acute cellular rejectio n.
DESIGN : A retro spective study.
SETTIN G: A referral ho spital center.
SAM PLE: 1 7 0 patients submitted to kidney transplantatio n fro m March 1 9 9 2 to January 1 9 9 7 . A standard technique fo r renal transplantatio n was used.
RESULTS: O f the 1 9 patients that develo ped lympho cele, 1 6 presented at least o ne episo de o f acute cell rejectio n (8 4 %), and were treated with methylpredniso lo ne. The relatio n between lympho cele and rejectio n was statistically sig nificant (p = 0 .0 4 ). Treatment o f lympho cele co nsisted o f perito neal marsupializ atio n in 3 patients (1 5 .3 %),
percutaneo us drainag e in 7 (3 6 .8 %), laparasco pic marsupializ atio n in 2 (1 0 .5 %), and co nservative treatment in 7 patients (3 6 .8 %). Evo lutio n was favo rable in 1 5 patients (7 8 .9 %), 1 patient (5 .3 %) died due to a cause unrelated to lympho cele, and 3 (1 5 .8 %) lo st the g raft due to immuno lo g ical facto rs. The averag e fo llo w-up perio d was 2 4 .5 mo nths.
CON CLUSION : The hig h incidence o f acute cell rejectio n in patients with lympho cele sug g ests a po ssible causal relatio nship between bo th co nditio ns.
KEY W ORDS: Kidney transplantatio n. Rejectio n. Lympho cele
in the iliac fo ssa, with dissectio n o f iliac vessels a nd b la d d e r d o me , a nd lig a ture s w ith no n-abso rbable sutures (co tto n 4 .0 ) and avo iding the use o f electro cautery.
The g raft was perfused with Euro -Co llins o r Belz er perfusio n so lutio ns fo r maintenance, fo llo wed by bench surg ery with special care in the hilum reg io n, and perfo rming vascular and lymphatic lig atures with no n-abso rbable sutures (co tto n 5 .0 ).
A trip le the ra p y w ith a z a thio p rine , p re d niso ne a nd c yc lo sp o rin w a s use d fo r immuno suppre ssio n. The dia g no stic o f a c ute cellular rejectio n was o btained by analysis o f the clinical data, which included an increase in se rum c re a tinine , a d e c re a se in d iure sis, eo sino philia and fever, after discarding vascular o b struc tio ns a nd uro lo g ic a l d iso rd e rs. A percutaneo us renal bio psy was also o btained if needed to validate the diag no sis. Acute cellular rejectio ns were treated with methylpredniso lo ne (1 g / d a y) fo r thre e d a ys a nd mo no c lo na l o rtho c lo ne a ntib o d y w a s use d (O KT3 ) in co rtico resistant rejectio n cases.
Pe lvic ultra so no g ra phy wa s c a rrie d o ut ro utine ly o n the fifth po sto pe ra tive da y a nd whenever clinically necessary. The perio d fo r diag no sing lympho celes by this imag ing metho d was fo ur to 9 3 po sto perative days (averag e 3 5 ). Lympho celes were defined as the presence o f pe rire na l fluid c o lle c tio n with a dia me te r g re a te r tha n 5 c m, dia g no se d a fte r the first p o sto p e ra tive w e e k. It w a s c la ssifie d a s sympto matic when asso ciated to lo cal and/ o r systemic sig ns and sympto ms.
Surg ical treatment was carried o ut in cases o f symp to ma tic lymp ho c e le w ith syste mic repercussio n. Surg ical treatment was preceded by aspirative percutaneo us puncture, g uided by ultraso und, and also bio chemical analysis and fluid culture.
W he ne ve r the re w a s e vid e nc e o f lympho cele recurrence witho ut sig ns o f infectio n, inte rna l d ra ina g e w a s p e rfo rme d (o p e n o r la pa ra sc o pic perito nea l ma rsupia liz a tio n). In case o f infected lympho cele, external drainag e was perfo rmed (clo sed drainag e system). The
averag e fo llo w-up perio d was 2 4 .5 mo nths. All re sults w e re sub mitte d to sta tistic a l analysis using Fisher’s exact test, co nsidering a p-value < 0 .0 5 as statistically sig nificant.
RESULTS
Amo ng the 1 7 0 kidney transplants studied, 1 0 6 patients (6 2 .5 %) develo ped acute cellular rejectio n and 1 9 (1 1 .2 %) had a diag no sis o f lympho cele within an averag e perio d o f 4 8 .5 days (rang e 9 to 1 5 6 ).
Table 1 sho ws that amo ng the 1 9 patients that develo ped lympho cele, 1 6 (8 4 %) had at least o ne episo de o f acute cellular rejectio n, and acute rejectio n was develo ped by 9 0 (5 9 .6 %) o f the remaining 1 5 1 patients that did no t present lymp ho c e le . The re la tio n fo und b e tw e e n lymp ho c e le a nd re je c tio n w a s sta tistic a lly sig nificant (p = 0 .0 4 ). Amo ng the sixteen patients with lympho cele that evo lved with acute cellular rejectio n, ten (6 2 .5 %) were submitted to renal p e rc uta ne o us b io p sy w ith d ia g no stic co nfirmatio n. The acute cellular rejectio n had c linic a l ma nifesta tio n b etween 3 to 5 0 da ys (a ve ra g e o f 1 0 d a ys) a nd the d ia g no sis o f lympho cele o ccurred between the 7th and the 6 4th day po st-surg ery (averag e o f 2 7 .5 days).
Co nsidering the 1 9 lympho celes, 1 2 (6 3 %) w e re sy mp to ma tic a nd ne e d e d surg ic a l interventio n, preceded by a neg ative culture in all cases. Thus, ultraso und g uided percutaneo us drainag e was carried o ut in 7 patients (3 6 .8 %), marsupializatio n in 3 (1 5 .7 %), and laparo sco pic marsupializ atio n in 2 (1 0 .5 %). The remaining 7 asympto matic patients (3 6 .8 %) were submitted to co nservative treatment with ultraso und and labo rato ry test fo llo w-up.
The treatment develo ped favo rably in 1 5 (7 8 .9 %) patients, 3 (1 5 .8 %) patients lo st the g raft due to immuno lo g ical causes, and o ne (5 .3 %) died due a cause no t related to the pro cedure. An averag e 2 4 .5 mo nth (rang e 3 to 5 3 mo nths) fo llo w-up perio d was maintained.
DISCUSSION
Kidne y tra nspla nta tio n is c urre ntly the treatment o f cho ice fo r patients in a terminal stag e o f chro nic kidney failure. This is no t, ho wever, a pro cedure free o f surg ical co mplicatio ns.3 ,7
Lympho cele is a surgical co mplicatio n with a described incidence between 0 .6 and 1 8 % o f p a tie nts sub mitte d to re na l tra nsp la nta tio n, p re se nting symp to ms in 3 6 % o f c a se s w ith perirenal fluid co llectio ns abo ve 1 0 0 ml.1 ,2 The va ria tio n in fre q ue nc y in diffe re nt tra nspla nt centers may be justified by the absence o f a sta nd a rd iz e d d e finitio n o f c o mp lic a te d lympho c e le , a s the ro utine a nd e a rly use o f ultra so no g ra p hy p ro vid e s a d ia g no sis o f lympho cele witho ut clinical co nsequences.5 ,8
The clinical o bservatio n that a sig nificant pro po rtio n o f the patients that presented acute c e llula r re je c tio n ha d de ve lo pe d lympho c e le sug g ests that there may be a direct asso ciatio n between these pro blems, which were co nsidered statistically sig nificant, but it has no t yet been po ssib le to e sta b lish a ny physio pa tho lo g ic a l cause directly related to these pro blems.
Data fro m the present study revealed a g e ne ra l inc id e nc e o f 1 1 . 2 % (1 9 / 1 7 0 ) o f lympho cele after renal transplantatio n, o f which 9 .4 % (1 6 / 1 7 0 ) had at least o ne episo de o f acute c e llula r re je c tio n, a nd o nly 1 . 7 % (3 / 1 7 0 )
presented lympho cele witho ut acute rejectio n. Braun et al9 repo rted 1 5 patients (1 8 .1 %) w ith ly mp ho c e le a mo ng 8 3 re na l tra nsp la nta tio ns. The se a utho rs hig hlig hte d facto rs that alter the lymphatic flo w o f either the g ra ft o r the re c e p to r (surg ic a l d isse c tio n, rejec tio n, use o f diuretic s a nd hig h do ses o f co rtico stero ids) as po ssible causes o f lympho cele. Po llak et al1 fo und 3 5 cases o f lympho cele (9 %) a nd o f the se , 1 3 (3 7 . 1 % ) w e re re la te d to episo des o f acute cellular rejectio n.
Kha uli e t a l5 sug g e ste d tha t a llo g ra ft re je c tio n is the mo st p o w e rful risk fa c to r c o ntrib uting to lymp ho c e le s fo llo w ing re na l tra nsp la nta tio n. In a d d itio n the se a utho rs emphasiz ed the impo rtance o f o ther so urces o f lympho celes, especially the care taken during surg ical techniques. Barro so et al1 0 emphasiz ed the impo rtance o f surg ical care, repo rting a rate o f 1 .1 % sympto matic lympho celes amo ng 3 5 6 re na l tra nsp la nta tio ns. Ho w e ve r no re la tio n between lympho cele and cellular rejectio n was repo rted in their cases.
Ano the r so urc e o f lymp h is the thre e plexuses o f the kidney g raft. Two are intra-renal plexuses, o ne aro und the kidney tubules and ano ther aro und the subcapsular reg io n. The third is an extra-renal plexus, alo ng the perirenal fat, which co mmunicates with the intra-renal plexus tha t dra ins hilum b ra nc hes into rena l vessels running to wards lateral ao rta branches and para-cava no dules. The lig atio n o f lymphatic branches e me rg ing fro m the g ra ft hilum c a n thus b e justified.5
Excluding surg ical facto rs, o ther causes o f lympho cele are allo g raft bio psies, arterio veno us fistula s, use o f d iure tic s, hig h d o se s o f co rtico stero ids and antico agulants, and especially episo des o f acute cellular rejectio n.5 ,1 1
Renal allo graft rejectio n is immuno lo gically me dia te d a nd invo lve s humo ra l a nd c e llula r respo nse. Cellular rejectio n is mo re frequent in the first three mo nths after transplantatio n, and is characterized by a set o f sig ns and sympto ms and impairment o f kidney functio n. The rejectio n g enerally respo nds quickly and satisfacto rily to co rtico stero ids, which in mo st cases revert the Table 1 - Profile of transplanted patients that
developed w ith or w ithout rejection and lymphocele*
Rejectio n
Lympho cele W ith W itho ut Total
Present 1 6 (8 4 %) 0 3 (1 6 %) 19 (11.2%)
Absent 9 0 6 1 15 1
Total 1 0 6 64 1 7 0
stimulated state o f the auto immune system that is manifested via intense inflammato ry pro cesses and increased lo cal flo w o f effluents.6 ,1 2
A p o ssib le me c ha nism to e xp la in the increased flo w o f lymph fro m the kidney during cellular rejectio n was demo nstrated by Pedersen and Mo ris.6 These autho rs used a sheep mo del in which the kidney was implanted in the neck o f the animals. They reco rded the flo w o f the effluent after cannulating lymph ducts o f the g raft. A 2 0 to 5 0 fo ld increase in flo w was o bserved during rejectio n, in co mpariso n to auto -transplant, indicating that an immuno lo g ical facto r related to the transplanted kidney may be invo lved in the g enesis o f the pro cess.
C a stilho e t a l1 1 o b se rve d e piso de s o f c e llula r re je c tio n b e fo re the d ia g no sis o f lympho cele in 6 0 % o f patients studied, while Kauli et al5 analyz ed the risk facto rs invo lved sta tistic a lly in lymp ho c e le in 1 1 8 kid ne y tra nspla nts, a nd o b served 6 .8 % sympto ma tic lympho celes up to 3 .7 years after transplantatio n. The la tte r a utho rs c o nc lude d tha t o nly a c ute c e llula r re je c tio n e p iso d e s w e re re la te d to lympho cele diag no sis.
The risk fa c to rs o b served in the present study, suc h a s the surg ic a l tec hniq ue a nd g ra ft b io p sy, d id no t sho w sta tistic a l sig nific a nc e w he n c o rre la te d to the p hysio p a tho lo g y o f lympho c ele, with the exc eptio n o f a c ute c ellula r rejec tio n (P = 0 .0 4 ) a nd po ssib ly thera peutic use o f c o rtic o stero ids (Ta b le 1 ).
The data o f the present study are similar to tho se o f o ther repo rts which have sho wn an inc id e nc e o f up to 7 5 % o f sy mp to ma tic lympho cele asso ciated with episo des o f cellular rejectio n treated with co rtico stero ids.1 ,2 ,5 These risk facto rs have also been described by o ther a utho rs,2 , 5 a ltho ug h the numb e r o f c e llula r re je c tio n e p iso d e s o r d o se s o f ste ro id s administered in each case2 ,5 are no t always clear. These fa c to rs ma y result in different types o f inflammato ry respo nse, justifying the increased ly mp ha tic flo w a nd g ra ft vo lume ,6 thus maintaining lympho cele in so me cases.
Diag no sis, co ntro l and manag ement o f
perirenal fluid co llectio n after transplantatio n no t o nly beco mes mo re efficient and safer with the use o f ultraso no g raphy5 ,1 1 but also co ntributes to c o mp lic a ting the d e finitio n in re la tio n to vo lume, sympto ms and clinical features. Khauli e t a l5 o b se rve d sp o nta ne o us re so lutio n o f lympho cele in 8 6 % o f cases, altho ug h Po llak et al5 analyz ed 3 8 6 kidney transplants and fo und 1 9 0 c a ses (4 9 %) o f perirena l c o llec tio ns, o f w hic h 9 8 p a tie nts (5 1 % ) w e re c linic a lly asympto matic and presented a vo lume belo w 5 0 ml that disappeared spo ntaneo usly during fo llo w-up. The rema ining pa tients (4 9 %), presented co llectio ns between 5 1 and 1 0 0 ml and had a sso cia ted o r suspected sympto ms o f cellula r re je c tio n, d e ma nd ing so me typ e o f surg ic a l appro ach.2 ,5
W henever lympho cele is sympto matic, the siz e o f the co llectio n, the perio d o f evo lutio n and the sympto ms sho uld be co nsidered, as well as excluding the presence o f infectio n caused by previo us puncture techniques. In the present study, we cho se to perfo rm surg ery in 1 2 patients (6 3 %) with sympto ma tic lympho c ele, i.e. 7 % o f the kidney transplants.
Acco rding to Amante et al,4 the treatment o f cho ice fo r draining sympto matic lympho cele is perito neal marsupializatio n, with a success rate b e tw e e n 8 0 a nd 9 0 % . The ma na g e me nt fo llo we d in the pre se nt study wa s a na lyz e d individua lly a nd presented po sitive results in 7 8 . 9 % o f the c a se s. W he n la p a ro sc o p ic marsupializatio n was cho sen (2 cases), a seco nd interventio n was necessary with a percutaneo us p unc ture in o ne c a se , a nd p e rito ne a l marsupializ atio n in ano ther.
Acco rding to data fro m G ruessner et al,1 1 laparo sco py is a feasible technique with a success ra te o f 6 4 % a nd sho uld b e use d ro utine ly.
Table 2 - Initial procedures in 1 9 patients that de-veloped lymphocele after k idney transplantation
Percutaneo us drainag e 7 (3 6 .8 %)
Perito neal marsupializatio n 3 (1 5 .7 %)
Laparo sco pic marsupializatio n 2 (1 0 .5 %)
RESUMO
CON TEX TO: A incidência de linfo cele em pacientes submetido s a transplante renal varia entre 0 ,6 e 1 8 % e vário s são o s fato res relacio nado s à sua etio lo g ia. A rejeição celular do alo enxerto renal tem sido descrita co mo um po ssível fato r etio ló g ic o das linfo celes. OBJETIVO: Verificar a po ssível asso ciação entre a o co rrência de linfo cele e a rejeição celular ag uda em transplante renais. TIPO DE ESTUDO: Estudo retro spectivo . AM OSTRA: 1 7 0 pacientes transplantado s no perío do de março de 1 9 9 2 a janeiro de 1 9 9 7 . LOCAL: Centro de referência ho spitalar. RESULTADOS: Do s 1 9 pacientes que evo luíram co m linfo cele, 1 6 apresentaram pelo meno s um episó dio de rejeição celular ag uda (8 4 %), to do s tratado s co m metilprediniso lo na. A relação entre linfo cele e rejeição fo i estatisticamente sig nificativa (p=0 .0 4 ). O tratamento da linfo cele fo i realiz ado através de marsupializ ação perito neal em 3 (1 5 ,3 %) pacientes, drenag em percutânea em 7 (3 6 .8 %), marsupializ ação laparo scó pica em 2 (1 0 ,5 %) e tratamento co nservado r em 7 (3 6 .8 %). A evo lução fo i favo rável em 1 5 (7 8 .9 %), 1 (5 ,3 %) fo i a ó bito po r causa não relacio nada à linfo cele e 3 (1 5 ,8 %) perderam o enxerto devido a fato res imuno ló g ico s. O perío do médio de aco mpanhamento desssa casuística fo i de 2 4 ,5 meses. CON CLUSÃO: A maio r freqüência de rejeição celular ag uda enco ntrada no presente estudo , em pacientes co m linfo cele, sug ere uma po ssível relação causal entre essas duas entidades.
PALAVRAS-CHAVE: Transplante renal. Rejeição . Linfo cele
Ho wever, it is a limited metho d when the co llectio n is anterio r o r supra-lateral to the g raft, asso ciated with a risk o f ure te ra l o r va sc ula r le sio n, o r intestinal o bstructio n, po ssibly recurring in 3 5 % o f cases.4 ,1 1 The co ntraindicatio n to incisio n o r la p a ro sc o p ic p e rito ne a l ma rsup ia liz a tio n o f lympho celes is the presence o f infectio n.
CONCLUSION
The hig he r fre q ue nc y o f a c ute c e llula r rejectio n fo und in o ur patients with lympho cele sug g ests a po ssible causal relatio n between the two co nditio ns. Further studies sho uld be carried o ut to define whether cellular rejectio n is a causal facto r fo r lympho cele o r if the asso ciatio n o nly relates to hig her do ses o f co rtico stero ids.
REFERENCES
1. Bry J, Hulld D, Bartus AS, Schweizer TR. Treatment o f recurrent lym p ho c e le s fo llo wing re nal transp lantatio n. Transp lantatio n 1990;49:477-80.
2. Po llak R, Varemis A, Maddux SM, Mo zes FM. The natural histo ry and therapy fo r perirenal fluid co llectio ns fo llo wing renal transplantatio n. J Uro l 1988;140:716-20.
3. Mundy AR, Po desta ML, Bewick M, Rudge CJ, Ellis FG. The uro lo gical co mplicatio n o f 1000 renal transplantatio ns. Br J Uro l 1986;53:397-402.
4. Am ante AJM, Kahan BD. Te c hnic al c o m p lic atio ns o f re nal transplantatio n. Surg Clin No rth Am 1994;75:1117-31.
5. Khauli RB, Sto ff JF, Lo vewell T, Ghavamian R, Baker S. Po st-transplant lympho celes: a critical lo o k into the risk facto rs, patho physio lo gy and management. J Uro l 1993;150:22-6.
6. Pedersen NC, Mo ris B. The ro le o f the lymphatic system in the rejectio n o f ho mo graft: a study o f lymph fro m renal transplants. J Exp Med 1970;131:936-69.
7. Sagalo wsky IA, Hinnant-Jr C, Co hen SM, Resnickz I. In: No nvascular co mplicatio ns o f renal transplantatio n - preo perative uro lo gy. 1st ed. Philadelphia: WB Saunders; 1995:19-25.
8. Castilho LN, Ferreira U, Liang LS, Frego nesi A, Netto -Jr NR. Linfo cele pó s transplante renal: tratamento video laparo scó pico : relato de cinco caso s e revisão de literatura. J Bras Uro l 1997;23:17-22.
9. Braun WE, Bano wsky LH, Straffo n RA, et al. Lympho celes asso ciated
with renal transplantatio n: repo rt o f 15 cases and review o f the literature. Am J Med 1974;57:714-29.
10. Barro so -Jr U, Lipay MAS, D’Avila CLR, et al. Co mplicacõ es cirúrgicas
pó s transplante renais: análise de 356 caso s. J Bras Uro l 1997;23:71-6.
11. Gruessner RWG, Faso la C, Benedetti E, et al. Laparo sco pic drainage
o f lympho cele after kidney transplantatio n: indicatio ns and limitatio ns. Surgery 1995:117;288-95.
12. Kalil J. Imuno lo gia do transplante renal. In: Princípio s de nefro lo gia e distúrbio s hidro eletro lítico s. 3
rd
ed. São Paulo : Savier; 1995:646-56.
M a rco Aurélio Silva Lipa y - PhD. Uro lo g y. Clinic o f Ho spital Beneficência Po rtug uesa. São Paulo , Braz il.
Irene de Lourdes N oronha - PhD. N ephro lo g y. Clinic o f Ho spital Beneficência Po rtug uesa. São Paulo , Braz il.
Arma ndo Vidonho Júnior - MD. N ephro lo g y. Clinic o f Ho spital Beneficência Po rtug uesa. São Paulo , Braz il.
Joã o Egídio Romã o Júnior - PhD. N ephro lo g y. Clinic o f Ho spital Beneficência Po rtug uesa. São Paulo , Braz il.
Joã o Ca rlos Ca mpa gna ri - PhD. Uro lo g y. Clinic o f Ho spital Beneficência Po rtug uesa. São Paulo , Braz il.
M iguel Srougi - MD, PhD. Uro lo g y (Chairman). Clinic o f Ho spital Beneficência Po rtug uesa. São Paulo , Braz il.
Sources of funding: N o t declared
Conflict of interest: N o t declared
La st received: 9 April 1 9 9 9
Accepted: 7 May 1 9 9 9
Address for correspondence:
