Experimental Transplantation of Freeze-Dried Homologous and Autologous Ureteral Segments

1961

Co,

EXPERiiVIEKTAL TRANSPLAKTATIOK OF FREEZE-DRIED H(J:VIOLOGOlJ:-< AKD URETERAL SECE\1ENTS R MARVIN HARVA!lD, JOSEPH A, CAlVIILLERI, PERRY W, NADH;

AND

JAMES F, GLENN

fi'rcnn the Section of Urolouy, Department of Sargery, Yale Universiiy School of Medfr£ne, New Haven, Conn,

The clinical and surgical problems rdated to disruption of the ureter have prompted considernblc experimental effort to reconstitute normal ureteral continuity Interruption of the normal channel may be caused by malignant or inflammatory disease, irradiation changes, surgical misadventure, or by congenital stricture, Acl vances in organ and tissl1e transplantation tedrniques suggest the possibility of ureteral transplantation, a theoretically ideal solution to the problem of replacement of damaged or dise1rned ureteral sPgments, The concept of ureternl reconstruction has fasC'inatcd investigators since the original in-, vestiga.tions of Boari in 1894, utilizing bowel seg;mPnts, glass tu bes, uterine horns, bladder and the carotid artery in attempts to reconstitute the ll!'eter, 1 Subsequent investigators have rmployed vein g;rnfts,2 sPgrnents of fallopian lyophilized arteries," fascial grafts with inert metal tubes,'' ilea! sl'gments with intact vascular pediclc, 6 and prolonged polyethylene tube splinting of un·trral and vrsscl grafts,? Ob, A,ccepted for publication :\larch 1, 196L Investigation under an institutional grant of the American Cancer 1 Spies, .J, W,, Jolnrnon, W, and Wilson, C. S,; Reconstruction of the ureter by a bladder flap, Proc, Soc, Biol & 30: 42.5-427. 1932. 2 Rosenberg, l\!L L, and G. A,; AutogenOllS vein grafts and venous in ureteral , An· experimentnl study, J, UroL, 70; 19.53. 'Schein, C, J., Saunders, A. IL and Hurwitt, ,K S, Experirnental reconstruction of meters: Substitution with aut.ogenons pedicled fallopian t.ube grafts, AMA Arch. Surg,, 73: 47-.53, 19.56, 4 SewelL W, H., Failure of freeze,dried homolog01rn arteries used as meternl grafts, J, UroL, 74: 600--602, 19.5.5. r, Lord, J W,, Jr,, Steflrn, P, L, and Stevens, A, R,: On bridging a gap in the meter by means of a free fascia] trnnsplnnt over a st.might vitalliurn tube· An experimental stw!y, J (;roL, 49: 249-2.54, l94:L D, W, and Fais, U G,: The ltse of small intestine a.s ureters J, Urol., 1952, , Experimental l'epair of ureters

servation of the tendency of split-thickness skrn grafts to develop and maintain a patent hmwn when introduced into the ubdominnl Jed to Politano's efforts to reconstitute the meter with split-thickness skin the most successful of such efforts to date. The problems involYed in surgical recorrntitu tion of the ureter arise i11 tbrel' areaB, the blood supply of the ureter is linear and i~ tlwn:foff interrupted by the interposition of any segment; peristalsis is similarly tissue other than autologous introducef, the factor of antigenicity; and non tissue induce a foreign body rcactim1 as wPll pm viding a focus for enerustation and cakulu,, formation, Autogenous arterial of th,, ureter have been embedded in intestinal t.unrn·fr, to attract new blood supply, 10 but wrtliout significant success. B011·el segments are"''."'"""'"''' in pro peristaltic fashion and maintain their 0\1 n peristalsis, but do not acquire ureteraI characteristics, 6 Antigen-antibody ,·w, N.,rrn not a present clinical problem, would b(,cumc serious consideration if the estahlishrnPnt of "ureter banks" became fea~ible . The, use metal, glass, plastic and fabric: remains impractical because of calculuf formatiou urinary leakuge; even the newer synthetic materials eventually act as a nidus (o, encrustations, This study was undertaken to evall1:1tc 1,Jw by polyethylene tubing ancl un:ternl n.nd ves,,el grnfts, AMA Arch. Snrg,, 68: 57-(il, HJ54, 8

Horton, C, W,, Georgiade, N,

n

Campheli,

F, H,, Masters, F, W. and Pickrell, L, behavior of split thickness mid demrn,l skin in the peritoneal cavity: An experirnental PlasC and Reconstruct,, finrg,, 12: 2(i\J-278, 9 Horton, C, E, and Poliiano, V, A,: lirnlcmi.l recornitruction with split skin grnfts: An expnri mental study, Pb.st, & Reconstruct. Surg,, 261-273. 19.55, ... lO Sarlders, A, R,, Schein, C, ,L and Hnrwilt K S,, The bridging of long uretend defof>l,s fresh autogenous arterial grnfts embedded submucosal intestinal tunnels, An experimen l.,i,] study, Brit,, J, UroL, 27: 245-25;1, l\)55,

385

TABLE

Animal

Procedure

Course

1. Results of ureteral segment transplantation

Survival

Pyelography

Histology

Gross Findings

Interpretation

----------!---------Homologous graft over! Catheter expelled, 28 days; I Sacrificed for final evaluaureteral catheter delivered normal litter, tion, 36 days splint; subcutaneous 35 days; no complications ureteral implant

Equal bilateral hydronephrosis, 36 days; gravid animal

Edema and adherence; lumen obliterated; segment visible; bilateral hydronephrosis

Nonfunctioning kidney, 29 days

Severe hydropyoureteroMarked inflammatory reacnephrosis; complete stricture tion; segment not identifiof segment able as such

Homologous graft overl Uncomplicated until I Expired suddenly of undeureteral catheter death; catheter extruded termined cause, 27 days splint into bladder, 20 days

Not accomplished

Small kidney; no evidence of obstruction; lumen patent

Homologous graft without splint

Uncomplicated

Sacrificed for final evaluation, 48 days

Nonfunctioning kidney, 14 days and 28 days

Marked hydroureteronephrosisl Marked inflammatory reacwith complete stricture of tion with obliteration of ureter segment

Failure

Homologous graft without splint

Vomiting and loss of appetite

Sacrificed for final evaluation, 44 days

Nonfunctioning kidney, 16 days

Lumen completely obstructed;! Inflammatory reaction with hydroureteronephrosis minimal fibrotic activity

Failure

Hon1ologous graft without splint

Uncomplicated

Sacrificed for final evaluation, 28 days

Nonfunctioning kidney, 19 days

Hydroureteronephrosis; segment obliterated; minimal scarring

Inflammatory reaction with minimal fibrotic activity

Failure

Autologous graft with-I Uncomplicated out splint

Sacrificed for final evaluation, 56 days

Nonfunctioning kidney, 56 days

Severe scarringi no hydroureteronephrosis; segment not identified

Complete obliteration of segment by marked fibrosis; renal atrophy

I Failure

Autologous graft with-1 Complete anuria; donor out splint ureter strictured

Expired in renal failure due to complete bilateral ureteral obstruction, 10 days

Not accomplished

Complete bilateral ureteral stricture with hydroureteronephrosis

Marked fibrosis; muscular layers of segment degenerated

Failure

Autologous graft with-I Uncomplicated out splint

Sacrificed for final evaluation, 60 days

Nonfunctioning kidney, 60 days

Moderate scarring; lumen of Segment patent and architecsegment patent; some hydroturally intact; moderate inureteronephrosis fla1nmatory reaction

Autologous graft with-I Uncomplicated out splint

Sacrificed for final evaluation, 55 days

Hydroureteronephrosis, marked; good concentration, 55 days

Segment patent with hydroureteronephrosis

I

Homologous graft over Catheter expelled, 20 days; ureteral catheter uncomplicated splint; subcutaneous implant with catheter

w

00

0,

10

11

12

I Sacrificed

for final evaluation, 32 days

Autologous graft ob- Septic course following first I Expired as result of sepsis, 7 Not accomplished procedure to obtain graft days after initial procedure tained but not transsegment planted Autologous graft with-1 Abscess at site of transout splint planted segment

Expired as result of sepsis, 5 days after final procedure

Not accomplished

Leukocytic infiltration, fibroblastic activity; some loss of architecture by segment

IVIinimal to moderate periureteritis; architecture of graft preserved

I Lumen

patent and architecture of segment preserved; moderate inflammatory reaction

Partial functional success

Failure

Apparent functional success

Qualified success

I Functional result

Not accomplished

Not accomplished

Inconclusive

Abscess and fistula at graft site; no hydroureteronephrosis

Not accomplished

Inconclusive

TRASSPL_\NTATION OF FREEZE-llRlED URE:'rEf{AL SEGMENTS

of ureternl n·(·
both homologous and autologom, donor ureters. body ff<,n' utilized to mmu,uze reaction and call'111us deposition. ;\UJTHODS AXD MA'l'1mIALS

H·ries of twdn· uclult mongrd dogs 1rns

selected for study, rli1·id1·cl into 2 groups of ti allim:ib each. ,\]] of tlif: exp,·rime11tal animals m'n: scree1wd wit.h prc()peratin: intnrn·Dous urn!2;r:rn1s, using 20 cc iiO pc:r cent hypaque, to ms11n· normal hact a1mtom>· and funetion. ] n the first group homologous nret.Prnl segment the sc·gment.s \I ere obtain eel from prepared dog 111·d,1-,r.s 11hich had lleen dehyclrnted with glyn·rin and r·:irbon dioxide, fl:vl1-fn,zc·n at minns-70°C., aud pn·s<·n·ecl at minn~-'l0° for period~ up to :,cv1•ral we<'h. I11 tlw sc·crltld group of animals, uret.eral graft. segment,, wen-: obtained from the nret1-'r at all initial operation, similarly pr<:p:rn·d and , m-,,F.,.,,.,, and subsequently irnplant<'d in the <·ontralateral kit ureter: donor

Frr; J. ~i, [ibrntic nn,ternl grnl\ ,egrnent., nnimal 10, \\'1th normal. :1

ureters IH're reanastomosccl 1·nd-to-P11d fishmontli technique ,Yithout splinting.

All ureternl graft Si'gments iYf-'r<' one centimeter in length, and \\ ere in the Jefi, mid-ureter, ,',posrcl The intact ureter was cli,'idcd obliquely, U:c· segment iHterposccl, aucl reanastomosi~ :H'l'1;u1 plishecJ bs multiple intcnnptr'd il-0 sutunis. 111 three animals grafts, size 4:F ureteral placed

In tbc remaining homografted auirnals all of tlw used, althollgh anastomosE', \i-t·n· rnade c1·1·r temporary splint, introduc(·d tbruugh :i pro,im:• I uri'tl'rotorny; in these casC's, the nret(·roton(1' left open as a dr:1inage \'i'll1' Roll tine l':1 tgut closure of wounds II as effi-'ded. .-i.ll np
n'rnainec!

1rnd,,,.

ohsr:n,ation Lrntil d<'mise ur ~acriffre for li1,a1 entluation 1'c1sr.011,ernr intrn.\·cnous was accornplishecl to asses, ,tm,tomic aud ological results of tlw prncnlure.s. Gross :i.,id histologie examination of ~c·guwm,, was made, obHerving; anastomo.,e~ and ureters and tissues.

and :inflammatory reaction. i.ofJn1u111ator:y chang:e(;

388

B. MARVIN HARVARD AND ASSOCIATES

Frn. 2. Intravenous urogram. A, animal 7 showing nonfunction of grafted side and hydronephrosis above site of donor segment on right. B, animal 10 showing moderate obstruction of donor right kidney and marked hydroureteronephrosis on recipient left side, though function appears to be adequate bilaterally. In 2 animals, segments of homologous ureter were implanted subcutaneously to investigate the .host response to such lyophilized implants. In one of the animals, the implanted segments contained portions of splinting catheter, left indwelling to determine the added effects of foreign body stimulation. The subcutaneous implants were removed and examined at 13 days and at 28 days. RESULTS

The results of this experimental study are outlined in table 1. Subcutaneously implanted ureteral segments, with or without splints, underwent severe inflammatory and fibrotic changes with obliteration of architecture. In the entire series, 4 animals had varying functional success of the ureteral graft implant. Six of the experimental trials were considered failures, and 2 animals did not survive long enough for evaluation. Gross and histologic examination of the grafted segments disclosed fibrosis and inflammatory reaction of varying degrees. It was the initial impression that the use of indwelling catheters as splints increased the amount of reaction and scarring; however, some excessive fibrosis developed in all animals in the series. In no instance could the reaction be attributed to antigenity; there was no appreciable difference

in the acceptance by the host of either the autologous or the homologous grafts. Histologic fate of the graft segments varied from complete obliteration of the segment by scarring to complete architectural preservation, the latter noted in three animals. Degeneration of the muscular layers of the grafts could be seen in one specimen. Figure 1 shows two extremes of reaction; one ureter is almost totally replaced by inflammatory cells and fibrosis, though the ghostarchitecture is still visible (animal 5); the second section reveals good architectural preservation of the graft segment, though with some inflammation (animal 10). Functional results of ureteral grafting were also variable, but in no instance was normal function attained. Two animals (1 and 10) maintained renal function as evidenced by continued excretion and concentration of iodide medium on pyelography, but most of the animals revealed nonfunction of the grafted side. In figure 2, intravenous urograms are reproduced; in animal 7 hydronephrosis developed on the donor side due to stricture, while the grafted ureter became completely sclerotic, resulting in renal atrophy; animal 10 maintained function of the grafted kidney, but marked hydronephrosis occurred. DISCUSSION

The results of this experimental effort to graft autologous and homologous ureteral segments are

TRANSPLANTATION OF FREEZE-DRIED URETERAL SEGiVlENTS

nut encouraging. Certain basic and persistent problems are appanmt. First, the of th<, linear bloodsupply of the ureter and the slow rcvascularization of the implanted ~egmrnt lead to atrophy and sclerosis of the graft segment. Despite this , satisfactory circulation developed in 2 animals for preservatiou of architecture of the segmrmt. The genera.I result of fibrosis, however, renal atrophy, was S(,vere hydronephrosis or dc]Jending probably upon the rapidity of obstruction of the 11rcter The second important fact.or encountered was the inkrruption of uu,ovnho,,o, leading to dilatation of the proximal system. Aperistalsis of the graft segment is unquestionably the cause of hydronephrosis seen in aninrnls 9 and 10, since the: lurnen and architecture of both these grafts were intact. It is conceivable that eventually mrnc: contractibility may be imparted to the graft segment by normal ureter, but this was not observed. Third, the question of splinting of the grafted ureter must be considered. -While the presenee of inchvrlling ureteral apparently increased tlrn amount of inflammator,1· reaction, this work and that of other investigators indicates that prolonged splinting is a necessity in such efforts to reconstruct the ureter. Prolonged

splinting would allow time for inhibit fibrotic stricture, and framework for regrowth of HlU8(·ular tissue ,,.-hid, would provide for peristaltic The fourth a.utogenous grafts have been introdur:e(L results of the present do not indicat,; significant difference in a.cceptauce of eiU1r·1autologous or homologous SUl\Hf'fARY

Autologous and homologous urnt.ernl sr-,grncrn; grafts have been in n series of mental animals. vVhile partial func:tioual histologic success was obtained in a few of animals, the result.s of m·eteral sc,gmcnt tran,,· plantation n,main discouraging. The· trehnicc.,! problems which result from ureternl segment grafts include blood supply and peristal8is, inflammatory 1,.11,J f-ibrotic reaction, and clegerwratiou of tbc segment. HydrourcteronPphrosis was the result, though renal atrophy was observ(•d some instances, presumably due to struction of the nreter. Brid of 1vcrc not beneficial in pn"venting theRe prolonged ureteral splinting was not plishecL