Results

Percutaneous Insertion of Ureteral Expansion Balloon

Percutaneous insertion was technically successful with satisfactory balloon placement in all five animals. The mean operative time required for balloon insertion was 52 ± 6 minutes, and there were no complications (Table 2).

TABLE 1 ■ Investigation Schedule

Timing

Laboratory: Complete blood count, metabolic

Prior to balloon insertion

profile, urinalysis and culture

Prior to augmentation ureterocystoplasty

Prior to euthanasia

Radiologic

Plain film

Weekly during balloon inflation

Prior to augmentation ureterocystoplasty

Cystogram

At 1-month follow-up

Prior to euthanasia

Intravenous urogram

Prior to euthanasia

Urodynamics

Prior to euthanasia

Cystoscopy

At 1-month follow-up (N = 2)

Prior to euthanasia

Histology

Light microscopy

During augmentation cystoplasty

At euthanasia

Transmission electron microscopy

During augmentation cystoplasty (N = 2)

Tissue cytokine assay (VEGF and TGF-P2)

During augmentation cystoplasty (N = 5)a

aSeven tissue biopsies were obtained from the five animals at the time of augmentation ureterocystoplasty for cytokine assay.

Chronic Ureteral Expansion

All five animals underwent successful ureteral expansion over a mean of 25 ± 1.4 days (Table 3). The mean final volume of the ureter was 177.1 ± 41.3 mL. The mean volume of fluid instilled was 12.7 ± 0.9 mL in the first week, 38.4 ± 4.3 mL in the second week, 66.2 ± 17.4 mL in the third week, and 59.8 ± 28.4 mL in the fourth week. The mean daily inflation volume was 1.8 ± 0.1 mL in the first week, 5.5 ± 0.6 mL in the second week, 11.3 ± 2.5 mL in the third week, and 16.1 ± 1.8 mL in the fourth week. All five awake animals readily tolerated the daily incremental instillation of dilute contrast solution without apparent pain or discomfort.

The inflation could be carried out without anesthesia or analgesia while the overnight fasting animal was busily eating.

Radiologic volumetric assessment of the ureteral balloon during the phase of ureteral expansion was commensurate with the amount of fluid instilled. We did not note any complications during ureteral expansion. Proximal urinary drainage through the fen-estrated channel of the ureteral expansion catheter was adequate in all five animals.

Laparoscopic Augmentation Ureterocystoplasty

Laparoscopic ureterocystoplasty was technically successful in all five animals without need for open conversion in any case. The mean operative time was 156 ± 41.1 minutes (range 115-210 minutes), and the mean estimated blood loss was 29 ± 16 mL (range 10-50 mL). One animal had a small-bowel serosal tear, which was readily suture repaired laparoscopically. Some periureteral adhesions were encountered in the vicinity of the expanded ureter, which could readily be lysed laparoscopically. Intraoperatively, at the time of ureterocystoplasty, the expanded ureter appeared thick and highly vascular, with areas of urothelial denudation. Intraoperative instillation of saline through the urethral catheter at the end of the ureterocystoplasty revealed a

TABLE2 ■ Intraoperative Data

Mean time for balloon insertion (min)

52 ± 10.6 (39-68)

Mean time for bladder augmentation (min)

156 ± 41.1 (115-210)

Estimated blood loss (mL)

29 ± 16 (10-50)

Subtotal cystectomy performed (N)

3

Ureteral stenting (N)

2

Urethral catheter (N)

5

Suprapubic catheter (N)

4

Open conversion (N)

0

Intraoperative complications (N)

Serosal bowel tear repaired laparoscopically (1)

The inflation could be carried out without anesthesia or analgesia while the overnight fasting animal was busily eating.

TABLE3 ■ Balloon Inflation Data

First week Second week Third week Fourth week

TABLE3 ■ Balloon Inflation Data

First week Second week Third week Fourth week

Mean daily

Mean daily

Mean daily

Mean daily

Final

Final

volume

Final

volume

Final

volume

Final

volume

Final

anticipated

aspirated

Duration

increase

volume

increase

volume

increase

volume

increase

volume

volume

volume

Animal

(days)

(mL)a

(mL)b

(mL)

(mL)

(mL)

(mL)

(mL)

(mL)

(mL)c

(mL)d

1

23

1.6 (0.5-3)

11.5

6.4 (3.5-10)

45

10 (10-10)

50

14.5 (14-15)

29

135.5

120

2

24

1.7 (0.5-3)

12

4.9 (3.5-9)

34

10 (10-10)

50

14.6 (14-15)

44

140

132

3

26

1.8 (1-3)

13

5(3.5-9)

35

10.8 (10-15)

65

18.6 (15-20)

93

206

200

4

26

1.9 (0.5-3)

13.5

5.6 (4-10)

39

13 (12-15)

91

17.4 (15-20)

87

230.5

216

5

26

1.9 (0.5-3)

13.5

5.6 (4-10)

39

12.5 (12-15)

75

15.3 (15-16)

46

173.5

170

Mean

25

1.8

12.7

5.5

38.4

11.3

66.2

16.1

59.8

177.1

167.6

aTotal volume of fluid introduced into balloon in a week divided by number of days injected. Although inflation was performed daily, a few days were skipped for logistical reasons.

bTotal volume of expansion achieved during week.

cEstimated amount of fluid in balloon at end of expansion process.

dActual volume of fluid aspirated from ureteral expansion balloon immediately prior to augmentation ureterocystoplasty.This volume was slightly less than the anticipated volume. There are two possible explanations: (1) some immeasurable fluid loss may occur during balloon inflation because of sudden movement of the animal, and (2) some fluid may not be completely aspirated from balloon.

watertight anastomosis in all five cases. Postoperative complications were seen in two animals: lower ureteral obstruction and pyelonephritis with urosepsis.

Urodynamic, Cystography, and Cystoscopy Data

Over a follow-up ranging from 15 days to 3 months, the mean bladder capacity was 574 ± 221.3 mL (range 380-940 mL). The Pves at maximum capacity was 14 ± 4.5 cmH2O (range 8-20 cm^O), and bladder compliance was 71.7mL/cmH2O (range 35.3-188 mL/cm^O). Uninhibited detrusor contractions were not evident on urodynamic evaluation in any of the five animals (Table 4). Cystography revealed ipsilateral reflux in four renal units: grade II in one animal, grade IV in two animals, and grade V in one animal (Fig. 7). At autopsy, one renal unit demonstrated lower-ureteral obstruction and therefore showed no reflux on cystography. There was no contralateral reflux in any renal unit. In all four refluxing units, the refluxed contrast drained from the kidney immediately after the bladder was emptied, thereby ruling out any ureteral obstruction. Additionally, the cystogram did not reveal contrast extravasation in any case.

Cystoscopy was performed in all animals at one month and at autopsy. By one month, the bladder revealed a fully regenerated mucosa in four animals; one animal euthanized at 15 days still had patchy areas of denuded mucosa.

Laboratory Data

Laboratory examination revealed minimal metabolic alterations in four animals. One animal that developed pyelonephritis and urosepsis had evidence of azotemia,

TABLE 4 ■ Radiologic Data

Urodynamicsb

Subtotal Cytograma Pves(cmH2O) Involuntary

TABLE 4 ■ Radiologic Data

Urodynamicsb

Subtotal Cytograma Pves(cmH2O) Involuntary

Animal

Follow-up (weeks)

(80%) cystectomy

Ipsilateral reflux (grade)c

Anastomotic leak?

Bladder capacity (mL)

Resting

Full capacity

Compliance (mL/cmH2O)

bladder contractions

1

2

No

2

No

600

3

20

35.3

Absent

2

4

No

4

No

380

2

12

38

Absent

3

8

Yes

-

No

940

3

8

188

Absent

4

12

Yes

4

No

430

4

12

53.8

Absent

5

12

Yes

5

No

520

6

18

43.3

Absent

Mean

-

-

-

-

574

3.6

14

71.7

-

aCystographic examination was performed at one month (N = 3) and at autopsy (N = 5) by injecting contrast through a urethral catheter. In all refluxing renal units, obstruction was ruled out by documentation of prompt drainage of contrast from the collecting system.

bUrodynamics, in the form of filling cystometrogram, was performed in each animal immediately prior to autopsy.The animal was anesthetized and placed supine on the table.The bladder was filled through a 6F urethral catheter, and intravesical pressure was recorded through a separate 6F urethral catheter connected to manometer tubing. Parameters recorded included total bladder capacity, resting and end filling pressures, bladder compliance, and involuntary detrusor contractions. cNo animal developed contralateral reflux.

FIGURE 7 ■ Autopsy photographs. (A) Augmented bladder and both renal units. Healed suture line between expanded ureteral patch (u) and native bladder (b) is seen (arrows). (B) Interior of augmented bladder shows demarcation (arrows) between expanded ureter (u) and native bladder (b). Notice complete epithelization of expanded ureteral patch.

FIGURE 7 ■ Autopsy photographs. (A) Augmented bladder and both renal units. Healed suture line between expanded ureteral patch (u) and native bladder (b) is seen (arrows). (B) Interior of augmented bladder shows demarcation (arrows) between expanded ureter (u) and native bladder (b). Notice complete epithelization of expanded ureteral patch.

Histologic examination of the expanded ureter harvested at the time of autopsy revealed persistent muscle hypertrophy and hyperplasia, a fully regenerated transitional epithelium, and variable amount of fibrosis.

hyponatremia, hyperkalemia, and acidosis (Table 5). The mean serum creatinine concentration was 1.3 ± 0.2 mg/dL at baseline, 0.9 ± 0.2 mg/dL at bladder augmentation, and 2.0 ± 0.9 mg/dL at euthanasia.

Autopsy Data

At autopsy, the ureteral patch appeared well vascularized, and the ureterocystoplasty suture line was healed in all five animals. The ipsilateral renal parenchyma appeared grossly normal in three cases, with pre-euthanasia intravenous urography revealing prompt opacification with mild hydronephrosis. One animal with a lower ureteral obstruction revealed thinning of parenchyma and poor function on intravenous urography. At autopsy, the obstruction was found to be the result of flimsy synechia formation at the junction where the upper, normal caliber ureter entered the expanded ureteral segment. The animal with pyelonephritis and urosepsis had a grossly scarred kidney that was nonfunctioning on intravenous urography.

Histologic Data

Histologic examination of the expanded ureter harvested at the time of autopsy revealed persistent muscle hypertrophy and hyperplasia, a fully regenerated transitional epithelium, and variable amount of fibrosis.

Light microscopic examination of biopsies of the expanded ureter obtained at the time of augmentation cystoplasty revealed muscle hypertrophy and hyperplasia, mucosal atrophy, and variable inflammatory infiltrate.

Electron Microscopic Data

Transmission electron microscopy performed on the ureteral tissue obtained at the time of laparoscopic augmentation revealed cellular evidence consistent with muscular hypertrophy and hyperplasia.

TABLE S ■ Serum Biochemical Data

Prior to ureteral balloon expansion

Prior to augmentation cystoplasty

Prior to euthanasia

Mean serum cretinine (mg/dL) Mean serum potassium (mEq/L) Mean serum sodium (mEq/L) Mean serum chloride (mEq/L) Mean serum CO2 (mEq/L) Mean anion gap Mean hemoglobin (mg/dL) Mean hematocrit (%)

1.3 ± 0.2 (1.1-1.4) 139.4 ± 3.3 (136-143) 4.3 ± 0.2 (4.1-4.5) 97.2 ± 3.4 (93-102)

27 ± 3.3 (24) 15.2 ± 3.9 (9-19) 11.6 ± 0.3 (11.3-12) 39.8 ± 2.0 (37.7-42.3)

0.9 ± 0.2 (0.7-1.1) 135.5 ± 7.0 (127-144) 4.4 ± 0.2 (4.1-4.6) 95.5 ± 6.5 (88-103) 27.8 ± 0.5 (27-28) 12.3 ± 1.0 (11-13) 9.6 ± 1.0 (8.7-10.9) 32.0 ± 3.4 (29.1-35.8)

2.0 ± 0.9 (1.4-3.4) 132.5 ± 9.7 (119-140) 4.7 ± 0.6 (4.1-5.4) 88 ± 18.9 (66-100) 24 ± 5.7 (16-19) 18.3 ± 11.4 (10-35) 10.3 ± 2.6 (8.8-14.1) 35.3 ± 8.1 (27.7-46.8)

After percutaneous placement of the balloon device, in-line expansion of the distal ureter was achieved on an outpatient basis over 23-38 days to a volume of upto 218 mL. Notably, all three patients did not require any analgesia during this entire expansion process.

The availability of a urothelium-lined, muscle-backed, vascularized, autogenous, in-line tissue material for purposes of augmentation, and possibly even replacement, of the urinary bladder would indeed be a major advance.

The ureter, with its transitional epithelium, is potentially an optimal tissue for bladder augmentation.

Growth Factor Assay Data

Preliminary data on growth factor expression in expanded ureteral tissue obtained and snap frozen at the time of augmentation ureterocystoplasty revealed a two to threefold increase in transforming growth factor-P2 (median, 44 pg/mL; range, 27-49 pg/mL) over controls (normal ureter, 16 pg/mL). There was no increase in vascular endothelial growth factor expression in the expanded ureteral tissue compared with control samples.

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