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  0041-1337/99/6806-731/0 T RANSPLANTATION  Vol. 68, 731–738, No. 6, September 27, 1999Copyright © 1999 by Lippincott Williams & Wilkins, Inc.  Printed in U.S.A. Transplantation  RAPID COMMUNICATIONS  A NEW, UNIQUE AND SIMPLE METHOD FOR URETERALIMPLANTATION IN KIDNEY RECIPIENTS WITH SMALL,DEFUNCTIONALIZED BLADDERS 1 O SCAR  S  ALVATIERRA  , J R ., 2-4 M INNIE  S  ARWAL , 3 S TEVEN  A  LEXANDER , 3 K  EVIN  V. L EMLEY  , 3 P ETER  Y  ORGIN , 3  A  MIRA   A  L -U ZRI , 5  A  MY   L U , 2 M  ARIA   M ILLAN , 2  AND  E DWARD  A  LFREY  2  Departments of Surgery and Pediatrics, Stanford University School of Medicine, Palo Alto, California 94304  Background.  Major, almost insurmountable, deter-rents exist to the use of the small capacity, defunction-alized, nonneurogenic urinary bladder in renal trans-plantation, namely, the technical difficulty inperforming a satisfactory ureteral implantation withconventional methods and the potential secondaryproblems with high grade ureteral reflux and obstruc-tion. Alternatives are less than ideal and includetransplantation into a bowel-augmented urinary blad-der with intermittent self-catheterization, ileal con-duit urinary diversion, or avoidance of transplanta-tion and relegating the patient to life-long dialysis.  Methods. Eight consecutive patients (ages 13 monthsto 29 years) with small, defunctionalized urinary blad-ders underwent a new method of intravesical implan-tation of the transplant ureter. The mean capacity of these bladders was 18.5  13.1 ml (range 6 to 45 ml),with the bladders defunctionalized for a mean81.6  24.3% of the patients’ total lifetime. The tech-niqueinvolvedplacementofthetransplantureterintoa shallow, mucosa-denuded, rectangular trough ex-tending from a superiorly placed ureteral hiatus dis-tally to the trigone. We hypothesized that the mucosalmargins on the two lateral aspects of the rectangulartrough would grow over the anterior surface of theureter until they met the advancing mucosal edgesfrom the contralateral side to form a natural neosub-mucosal tunnel.  Results.  Posttransplantation cystoscopic examina-tion demonstrated bladder mucosal regeneration andgrowth over the ureter, confirming the spontaneousdevelopment of a good length neosubmucosal tunnel. All patients demonstrated no evidence of ureteral re-flux or ureteral obstruction, whereas an immediateprior cohort of four consecutive patients with bladdercapacities  < 30 ml showed that three of four had ure-teralreflux(  P  0.02)andfouroffourdevelopedhydro-nephrosis (  P  0.002). All urinary bladders in thepresent cohort enlarged to expected normal or near-normal capacities. Serum creatinines were stablethroughout the entire follow-up period, with the ex-ception of one patient who had rejection episodes.Two patients had urinary tract infections posttrans-plantation, but there were no episodes of acute pyelo-nephritis. Conclusions.  This novel technique for ureteral im-plantationsuccessfullycapitalizesontheregenerativepotential of the bladder mucosa, resulting in a physi-ological, anatomically natural, and very effective neo-submucosal tunnel. It appears to guarantee successagainst both ureteral reflux and obstruction, no mat-ter how small the urinary bladder, and offers no hin-drance to enlarging the bladder to near normal capac-ityposttransplantation.Theimplantationtechniqueissimple and safe, and its use should eliminate the re-luctance to use these bladders. Moreover, this proce-dure offers a major incentive for the successful reha-bilitation of small, defunctionalized, nonneurogenicbladders after kidney transplantation. Major deterrents to the use of the small capacity, defunc-tionalized, nonneurogenic urinary bladder in renal trans-plantation have been the enormous technical difficulty inperforming a satisfactory ureteral implantation, the subse-quent potential problems with high-grade ureteral reflux orobstruction, and the belief that the small, contracted urinarybladder cannot be rehabilitated. Bladder augmentation withintermittent self-catheterization has been a preferred ap-proach ( 1–5 ); however, it has its inherent problems and is byno means the ideal solution ( 6–14 ). Ileal conduit urinarydiversion has been another alternative for urinary drainageof the transplanted kidney ( 15, 16 ). The potential technical,management, and morbidity problems involving these proce-dures can lead to a reluctance to transplant these patients,forcing them to life-long dialysis.Only a few reported attempts have been made to use andrehabilitate the small, defunctionalized bladder after renaltransplantation ( 17–21 ). Implantation of the transplant ure-ter into very small bladders has been generally accomplishedextravesically because of the technical difficulty and virtual 1 This work was supported in part by the Lucile Packard Founda-tion. 2 Department of Surgery, Stanford University School of Medicine. 3 Department of Pediatrics, Stanford University School of Medi-cine. 4  Address correspondence to: Oscar Salvatierra, Jr., MD, StanfordUniversityMedicalCenter,703WelchRoad,SuiteH-2,PaloAlto,CA 94304. 5 Current address: University of Arizona Medical Center, Depart-ment of Pediatrics, Health Sciences Center, 1501 N. Campbell Ave-nue, Tucson, AZ 85720.731  impossibility of constructing an adequate submucosal tunnelby an intravesical approach. The extravesical approach, how-ever, most often results in a mere right-angled, direct, “plug-in” attachment to the bladder. This, in turn, can predisposethe development of ureteral reflux from increased intravesi-cal pressure during the period of bladder enlargement (  22 ),and also, has the potential for ureteral obstruction fromangulation of the distal ureter after superior migration of thetransplant ureteral orifice with bladder enlargement (  23 ).We describe a new, relatively simple, fairly foolproof tech-nique for the implantation of the transplant ureter intosmall, defunctionalized, nonneurogenic urinary bladders,without the potential problems encountered with previousmethods of ureteral management in patients with these blad-ders. This technique capitalizes on the regenerative potentialof the bladder mucosa to form a natural neosubmucosal tun-nel. PATIENTS AND METHODSDuring a 1-year period from December 1997, eight consecutivepatients with small, defunctionalized, nonneurogenic urinary blad-ders, six of which had capacities less than 20 ml, underwent a newmethod of intravesical implantation of the transplant ureter. Thetechnique for ureteral implantation is described below. The patientweight range at the time of transplantation was from 9.5 to 62 kg. Alleight patients were males, with a mean follow-up period of 8.1  3.7months (range 3 to 15 months) posttransplantation. The other sa-lient features of these patients are described in Table 1 and includeage at the time of transplantation; etiology of end-stage renal dis-ease; urinary bladder capacity at the time of transplantation; thepercentage of each patient’s total lifetime to the time of transplan-tation during which the urinary bladder was completely defunction-alized (absolutely no urine in bladder); panel reactive antibody at thetime of transplantation; and kidney donor category.Pretransplantation, all patients had a pertinent history and neu-rological examination directed at the lumbar and sacral nervousoutflow to exclude any reason for neurogenic bladder dysfunction,although all patients with posterior urethral valves also had cys-tourethroscopy to rule out any residual obstructive valves. Urody-namic studies were not performed, because they have proven unre-liable in our work in determining the potential for rehabilitation of these small bladders. Posttransplantation, all patients had cysto-grams performed to evaluate for presence of vesicoureteral reflux at2 to 3 months, as well as with any dilation of the renal pelvis orureter by ultrasound. Serial renal ultrasounds were obtained atapproximately 2-month intervals until 6 months posttransplanta-tion, and with any increase of serum creatinine, to evaluate forevidence of hydronephrosis, ureteral dilatation, and to follow theprogress of bladder enlargement. Serum creatinines and urine cul-tures were closely monitored throughout the entire posttransplantfollow-up. In four patients, where informed consent could be ob-tained for strictly study purposes, cystoscopy under anesthesia wasperformed during the period of progressive bladder enlargement,after removal of the cystostomy catheter. A retrospective analysis of ureteral reflux and hydronephrosis was also performed in the onlyfour patients with bladder capacities   30 ml who received kidneytransplants during the 3-year period immediately preceding thepresent series. Immunosuppression was initially cyclosporine-basedin each patient, as previously reported (  21 ). Means are reported  SDThe Fisher’s test was used to calculate statistical significance. Technique of ureteral implantation.  Our new technique of ure-teral implantation adhered to the basic principles advocated byTanagho (  23 ) for an anatomically competent ureterovesical junction.The urinary bladder was entered through a vertical cystotomy inci-sion in all cases. In patients with obstructive uropathy from posteriorurethral valves, considerable cicatricial reaction from multiple pre- vious surgeries and infection was usually found to encapsulate thebladder. This scar tissue was removed from the dome and anteriorsurface of the bladder, as well as on the ipsilateral side of theureteral implantation, so that the bladder would have no restrictionfor subsequent expansion with voiding posttransplantation. A gen-erous hiatus for the ureter was created through the bladder wall, asclose as possible to the superior posterior-lateral surface on the baseof the bladder (  23 ). This hiatus was placed in diagonal fashion,rather than at a direct, right-angle through the bladder wall, so asto avoid ureteral kinking or obstruction (  24 ) (Fig. 1A). The newureteral hiatus was adequately sized so as to allow the ureter to becomfortably pulled through into the lumen of the bladder withoutany drag. In addition, care was taken to taper the inferior intra- vesical margin of the hiatus, as well as the superior extravesicalmargin, to assure a completely smooth course for the ureter and toavoid any ureteral angulation at these two corners with the risk of subsequent obstruction (arrows in Fig. 1A). These steps werebelieved particularly important in thick-walled bladders from pos-terior urethral valves.Before bringing the ureter into the bladder lumen, a shallow,rectangular trough was constructed from the new ureteral hiatusdistally to the trigone near the bladder neck. The ultimate direction varied, depending on the size of the urinary bladder. In the verysmall bladders, the distal end of this trough crossed the midline. Thewidth of the trough was approximately 0.5 to 0.7 cm, although thelength was as close to 2 cm as possible. The trough was created byexcising bladder mucosa to bare detrusor muscle in all cases. Inthickened and scarred bladders from posterior urethral valves, asmall amount of the underlying detrusor was also excised to assureT  ABLE  1. Patient characteristics Patient Age attransplantESRDdiagnosisBladdercapacity (ml)% of patient’s lifetimethat bladder wasdefunctionalized (%)PRA (%) Kidneydonor 1 6 yr PUV 45 86 0 CAD2 12 yr PUV 19 100 10 LRD3 13 mo ARPKD 14 69 0 LRD4 29 mo PUV 6 100 0 LRD5 29 yr PUV 16 97 100 CAD6 13 mo ARPKD 10 31 0 LRD7 29 mo Corticalnecrosis8 100 0 LRD8 27 yr PUV 30 70 7 CADMean 10.1  11.6 yr 18.5  13.1 81.6  24.3ESRD, end-stage renal disease; PUV, posterior urethral valves; ARPKD, autosomal recessive polycystic kidney disease, neonatal type;CAD, cadaver donor transplant; LRD, living related donor transplant; PRA, panel reactive antibody.TRANSPLANTATION 732  Vol. 68, No. 6  the creation of an adequate, shallow trough. This appeared to insurea good, tailored, anatomic bed for the distal ureter. After developing the rectangular trough, the distal ureter wasthen brought through the ureteral hiatus into the bladder lumen andlaid in the trough (Fig. 1B). Distally, the ureter was spatulated on itsanterior surface for approximately 0.4 cm. The distal end of theureter was then securely anchored at the distal end of the trough tothe trigone (  23 ) with three sutures of 5-zero or 6-zero monofilamentpolyglyconate or braided polyglycolic acid. On the ureteral side, twosutures were placed near the distal corners of the spatulation, and athird was placed in between. On the bladder side, each suture in-cluded a good segment of muscle, as well as mucosa, to assureadequate and secure anchoring. One suture of 6-zero poly-glyconate or polyglycolic acid was sometimes placed on each side of the ureter to approximate loose periureteric tissue to the margins of the bladder mucosa at the lateral aspects of the rectangular trough. A ureteral stent was then passed superiorly into the transplantureter to further assure good alignment with a straight, unkinkedcourse through the bladder (Fig. 1C). The stent was either a softdouble-J stent or a feeding tube with two or three additional smallapertures in the portion that would reside in the renal pelvis. Ineither case, the distal end of the stent was divided and removed, asthe small bladder lumen would usually not accommodate more than1–2 cm of the stent outside the ureteral orifice. A Malecot 4-wing cystostomy catheter (14 French in infants and 20 French in adults)was then placed with the catheter brought through a separate stabwound in the bladder wall, and not through the cystotomy sutureline. A Malecot 4-wing catheter is the only catheter that should beused, because its four wings can protect and prevent the smallbladder from collapsing on the single, large exit aperture of thecatheter and, thus, always assure free drainage of urine, even in thepresence of some hematuria. A Pezzer catheter should not be usedbecause its small apertures at the periphery of the rubber disc can beeasily occluded by the surrounding wall of the small capacity bladderand risk bladder perforation with diuresis (discussed in  Complica-tions ). The ureteral stent is secured to the end of the Malecot cath-eter with a 4-zero polyglyconate suture.The anterior cystotomy incision was then closed with a singlelayer closure of 2-zero to 4-zero polyglyconate depending on thethicknessofthebladderwall.Asecondlayerappearedundesirableinthese small bladders, as it could further reduce the lumen of thebladder.However,thepresenceofaMalecotcystostomytubeassuredgood drainage without significant risk of urine leak. After closing theanterior cystotomy incision, the anterior bladder wall adjacent to thecystotomy tube was fixed, as best as possible, considering the smallsize of the bladder, to the overlying rectus muscle with 3-zero or4-zero polyglyconate sutures to eliminate dead space in this area.Cystostomy drainage was maintained for at least 2 weeks, the actualtime was dependent on the size and pathology of the urinary bladder.The rationale for 2 weeks’ cystostomy drainage was to optimizehealing and to allow adequate early development of the neosubmu-cosal tunnel, before subjecting the small capacity bladder to highintravesical voiding pressures. On removal of the cystostomy tube,the previously attached ureteral stent was also automatically re-moved. Foley urethral catheter drainage after removal of the cystos-tomy tube was usually not indicated, as the cystostomy tract sealedwithin 12 hr in seven patients. Urine drainage through the cystos-tomy tract persisted in only one of our eight patients, but ceased oninstituting urethral catheter drainage for several days.RESULTS Complications.  There were no posttransplant surgicalcomplications during the entire follow-up period, with theexception of patient 6, which required early return to theoperating room because of urinary extravasation from aspontaneous perforation at the dome of his small bladder.This is the only patient with which a Pezzer suprapubiccatheter was used and, unfortunately, this resulted in theocclusion of the peripheral apertures of the catheter by thesmall bladder. The anterior cystotomy suture line and thecystostomy site were intact, without any urine leakage fromthese sites. After bladder repair and replacement of thePezzer catheter with a Malecot catheter, this patient had acompletely uneventful posttransplant course. Ureteral reflux and hydronephrosis.  Cystograms per-formed showed no evidence of vesicoureteral reflux in all F IGURE  1. A, Depiction of the denuded, shallow, rectangular trough for the intravesical ureter and the correct diagonal ureteral hiatusthrough the thickened bladder wall. The arrows point to the two corners of the hiatus that require tapering. B, The transplant ureter is visualized passing through the diagonal ureteral hiatus and laid on the rectangular trough. Three sutures fixate its spatulated end to thearea of the bladder trigone. An optional suture incorporating only loose periureteric tissue to lateral mucosal margin is also shown. C, A Malecot 4-wing cystostomy catheter and ureteral stent in place. The ureteral stent is secured to the end of the Malecot catheter, so that whenthe cystostomy tube is removed, the ureteral stent will be pulled with it, eliminating the need for cystoscopic removal.SALVATIERRA ET AL.  September 27, 1999  733  eight patients. Serial renal ultrasounds showed no evidenceof significant hydronephrosis or dilated transplant ureter.Patient 2 received a right kidney from his multiparousmother with a preexisting, large, dilated renal pelvis anddilated ureter. This preexisting dilatation mostly resolved onfollow-up renal ultrasound monitoring and this patient’s lat-est serum creatinine at 11 months posttransplantation was1.0 mg/dl. Patient 4 was the only patient with transientminimal dilatation of the renal pelvis and ureter at 6 weeksposttransplantation, during the period of bladder enlarge-ment. Follow-up ultrasound examination was completelynormal, while the latest serum creatinine at 8 months re-mained stable at 0.4 mg/dl. The ultrasound results in oureight patients have thus consistently documented absence of anatomic ureteral obstruction and also absence of significantfunctional interference to ureteral emptying from increasedintravesical pressure during the period of bladder enlarge-ment.Retrospective analysis of the immediately previous fourconsecutive transplant recipients with bladder capacities  30 ml revealed that three of four had modest to moderatereflux (  P  0.02 in comparison with our series) and four of fourhad modest to moderate hydronephrosis (  P  0.002 in compar-ison with our series). One patient required surgical interven-tion for relief of obstruction, although the other three pa-tients are being followed conservatively for reflux. Thedegree of reflux and hydronephrosis decreased in two pa-tients within 1 year, whereas the third patient will probablyrequire ureteral reimplantation in the future. All four pa-tients demonstrated elevated serum creatinines (range 0.3 to0.6 mg/dl above baseline) with peak severity of their hydro-nephrosis. Cystoscopic findings.  Follow-up cystoscopies under anes-thesia were performed on four patients where consent couldbe obtained, to evaluate and study the intravesical portion of the transplant ureter. These examinations all demonstratedbladder mucosal regeneration and growth over the ureter,confirming the spontaneous development of a neosubmucosaltunnel. The intravesical ureter was almost completely cov-ered by normal-appearing neomucosa by 1 month posttrans-plantation, and completely so by 2 months.The intravesical portion of the transplant ureter appearedto be only slightly longer than that at the time of transplan-tation, commensurate with the increase in bladder capacityat the time of the cystoscopic examination. Constant obser- vation of each ureter, although the urinary bladder was filledduring the cystoscopic examination, demonstrated ureteralcompression with bladder filling, and evidence of adequatemuscular backing to achieve this result. This, in turn, ap-peared to confirm the presence of a valve-like mechanismthat would prevent ureteral reflux. This compression was notexcessive or obstructive, as indigo carmine administered i.v.was visualized to freely efflux from the ureteral orifice, with-out apparent impedance to the flow of urine from the ureter.In fact, normal rhythmic, muscular contractions of the entireintravesical ureter, with good peristaltic waves, were visual-ized. This was not unexpected, as the donor kidneys all hadgood, healthy ureters, with subsequent good preservation of distal ureteral blood supply by the described technique.  Renal function and urinary tract infections.  All patientshad immediate, excellent graft function and stable creat-inines throughout the entire follow-up period, with the ex-ception of patient 5, which represented the only patient inthe series with rejection episodes (Table 2). Two patients hadurinary infections, but these infections were without clinical,acute pyelonephritis, presumably because of nonrefluxing transplant ureters. Patient 1 had several urinary infections,which were secondary to fecal contamination of a perinealurethrostomy, that was necessary because of complete oblit-eration and scarring of his bulbous urethra after resection of posterior urethral valves shortly after birth. Closure of theperineal urethrostomy and urethral reconstruction was sub-sequently carried out. Another patient was treated for asingle, asymptomatic positive culture.  Bladder enlargement.  All urinary bladders enlarged to ex-pected normal or near-normal capacity by 6 months post-transplantation, commensurate with the age and size of thepatients who had a weight range from 9.5 to 62 kg (  25 ) (Table3). Residual urines in the nonposterior urethral valve blad-ders were normal, although residual urines in the valvebladders were normal to acceptable at less than 15% of blad-der capacity. Case report.  Patient 5 was selected for further detaileddescription, because the donor kidney had a double ureterthat provided much greater ureteral surface for coverage bybladder mucosa regeneration. This case, therefore, allowedus to best test the hypothesis that an effective neosubmuco-sal tunnel develops after the described technique.This patient underwent bilateral cutaneous ureterosto-mies shortly after birth, because of severe obstructive poste-rior urethral valves. At age 16, the patient had his defunc-tionalized urinary bladder augmented with ileum. This wasfollowed shortly thereafter with two kidney transplants: thefirst failed early because of renal artery thrombosis, but thesecond failed because of   Pseudomonas  pyocystis in the aug-mented bladder, and secondary  Pseudomonas  transplant py-onephrosis, and severe  Pseudomonas  urethritis. The patientunderwent transplant nephrectomy and excision of the blad-der augment, to control sepsis. Because of the two failedtransplants and multiple blood transfusions, the patient be- T  ABLE  2. Renal function; serum creatinines (mg/dl) Case At 3 mo At 6 mo Latest after 6 mo 1 0.5 0.5 0.5 (15 mo)2 1.4 1.2 1.0 (11 mo)3 0.4 0.4 0.4 (9 mo)4 0.4 0.4 0.4 (8 mo)5 1.8 2.3 2.1 (8 mo)6 0.3 0.37 0.5 0.5 (5 mo)8 1.2T  ABLE  3. Bladder capacity Case At transplantation (ml) At 3 mo a (ml) At 6 mo a (ml) 1 45 160 2152 19 165 2603 14 70 1004 6 60 955 16 210 2906 10 85 1107 8 408 30 270 a Determined to the nearest 5 ml.TRANSPLANTATION 734  Vol. 68, No. 6  came 100% sensitized and was then referred to Stanford. Thepatient waited 11 years, until a cross-match negative cadaverkidney became available, as a 0-antigen mismatch. At thetime of transplantation, the bladder could not be enteredbecause of bleeding and its very small size, so the ureterswere brought out to the skin as a cutaneous ureterostomy.Postoperative consultation was then obtained from the firstauthor, after which the patient was reexplored 1 week post-transplantation through the same transplant wound. Thecutaneous ureterostomy was taken down by dividing thedouble ureters adjacent to the abdominal wall in the extra-peritoneal space. This was followed by implantation of thedouble ureters in juxtaposition into the small, contractedurinary bladder. Two ureteral stents were used and the rect-angular trough bed was wider than usual, so as to accommo-date the double ureters side by side. At the beginning of the same anesthetic procedure, butbefore reopening the transplant wound, the patient wasfound to have approximately 15 severe, strictured areas inthe bulbous urethra from his previous, severe  Pseudomonas urethritis. These could not be dilated by the usual means, sothey were all individually visually incised with a visual ure-throtome. After urethral catheterization, an intraoperativeretrograde cystogram was obtained, before the implantationof the double ureters and is shown as the inset in Figure 2.Figure 2 also demonstrates the posttransplantation blad-der configuration when bladder capacity had achieved 210 mland shows no evidence of reflux to either of the two juxta-posed ureters. Figure 3 is a cystoscopic photograph of theintravesical double ureters, demonstrating coverage of thedouble ureters by regenerated bladder mucosa. Figure 4 is ahead-on view of one of the two ureteral orifices, showing widepatency and good efflux of i.v. administered indigo carmine.Eight serial renal ultrasounds, performed at less than 1month intervals during the first 6 months posttransplanta-tion showed no evidence whatsoever of any hydronephrosis toeither of the two renal segments drained by the two separateureters.This patient has had an uneventful postoperative course tothe present time, with the exception of three biopsy-provenrejection episodes and the need for periodic urethral dilationto maintain patency of his bulbous urethra. F IGURE  2. Retrograde cystograms at the time of double ureteralimplantation 1 week posttransplantation (inset), and at 3 monthsposttransplantation with the bladder capacity increased to 210 ml.The arrows point to a bladder diverticulum that was located superiorto the dome of the small, defunctionalized bladder and its laterpartial concealment by the bladder enlargement. The defunctional-ized bladder (inset) shows a capacity that is approximately threetimes the inflated 5-ml Foley balloon. The staples to the right of thebladder are from the kidney transplant surgery performed 1 weekbefore reoperation for the double ureteral implantation.F IGURE  3. Cystoscopic photograph demonstrates a wide, longitudi-nal mound that represents neomucosa covering the elevated doubleureters within the dotted line. The larger arrows on the left point tothe direction of the two ureteral orifices that are not seen and arelocated distal to the bottom margin of the photograph. The upper-most portion of the dotted encirclement near the top of the figurerepresents the area where the two ureters were brought through thebladder wall hiatus. Note the vascular-rich neomucosa extending from the right lateral margin of the former rectangular trough ontothe ureteral mound (dotted line on right demarcates boundary of normal bladder mucosa and neomucosa on ureter). The smaller ar-rows are on, and point to, the edges of a vascularized, triangularmucosal bridge that is seen from a different perspective in Figure 4.SALVATIERRA ET AL.  September 27, 1999  735
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