Renal Failure Associated with the Use of Thio-Tepa

Vol. 110, November

THE JOURNAL OF UROLOGY

Copyright © 1973 by The Williams & Wilkins Co.

Printed in U.S.A.

RENAL FAILURE ASSOCIATED WITH THE USE OF THIO-TEPA PAUL F. SCHELLHAMMER From the Section of Urology, Surgical Service, McGuire Veterans Administration Hospital, Richmond, Virginia

Severe fibrotic contracture of the bl adder, causing renal failure because of vesicoureteral reflux or ureteral obstruction, is a common complication of intracavitary radiation for vesical neoplasia. '· 2 Investigators using thio-tepa for the treatment of superficial vesical neoplasms have not reported similar complications. 3 • 4 A case in which extensive bladder reaction to thio-tepa led to partial ureteral obstruction and compromised renal function is reported herein.

aminations were normal. Urinalysis demonstrated many red and occasional white blood cells. Specific gravity was 1.025. A complete blood count (CBC) was normal, blood urea nitrogen (BUN) was 20 mg. per cent and serum creatinine was 1.2 mg. per cent. Arterial blood gases (room air) revealed an oxygen pressure of 58 mm, Hg, carbon dioxide pressure of 39 mm, Hg and pH equal to 7.41. An excretory urogram (IVP) showed bilateral function, A filling defect was noted in the left renal pelvis and was

FIG. 1 CASE REPORT

confirmed by retrograde pyelography on several occasions (fig. 1, A). Cystoscopy revealed papillary lesions at the bladder base and dome. Diagnosis was transitional cell carcinoma of the pelvis with seeding to the bladder. Left nephrectomy and partial ureterectomy were performed. Hypotension during the procedure contraindicated a second incision to excise the lower ureter with a cuff of bladder. Transurethral resection of the bladder lesions was undertaken 2 weeks later. Microscopic examination of the renal pelvis revealed chronic inflammation with adherent clot. There was no evidence of malignancy. Well differentiated, noninvasive transitional cell carcinoma was found in the bladder. The blood clot in the microscopically normal renal pelvis had possibly originated in the bladder, although a single cystourethrogram had shown no reflux. The patient was well when discharged from the hospital. He returned 2 months later for IVP and

J, A., 227073875, a 76-year-old white man with severe chronic obstructive pulmonary disease, had a 3-month history of intermittent gross hematuria, Abdominal examination was negative for tenderness, organomegaly or mass and there was no flank tenderness. The genital, rectal and prostatic ex-

Accepted for publication May 18, 1973. 1 Wallace, D. M.: Intracavitary radiation for multiple non-infiltrating bladder tumours. Brit. J. Ural., 43: 177, 1971. 2 Abbassian, A. and Wallace, D. M.: Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. J. Ural., 96: 461, 1966. 'Veenema, R. J,, Dean, A. L., Jr., Roberts, M., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillation of thiotepa. J. Ural., 88: 60, 1962. 'Jones, H. C. and Swinney, J,: Thio-tepa in the treatment of tumours of the bladder. Lancet, 2: 615,

1961. 498

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499

FIG. 2

cystoscopy. IVP revealed a normal right collecting system and ureter (fig. 1, B). demonstrated recurrent lesions of the dome and base of the bladder. Bimanual examination revealed no masses. BUN was 24 mg. per cent and creatinine 1.6 mg. per cent. Transurethral resection of the bladder lesions was performed without damage to the right ureteral orifice and non-invasive transitional cell carcinoma was found. Treatment with thio-tepa was initiated a month after the bladder resection. A regimen of 60 mg. in 60 ml. normal saline, instilled by a catheter and retained for 30 to 60 minutes before being voided, was scheduled on a weekly basis for 6 weeks. CBC and platelet count were performed before . Four instillations were administered without local symptoms and without changes in peripheral blood counts. The white blood count (WBC) before the fifth instillation was 5,000 and the platelet count was 95,000. The patient complained of urgency, frequency and dysuria. Thio-tepa was withheld. Urine culture yielded more than 10' Escherichia coli per milliliter. resolved with sulfa toscopy revealed areas of without evidence of tumor. BUN was 34 mg. per cent and serum creatinine was 2.1 mg. per cent. Treatment was reinstituted a ·week later when local symptoms had subsided and peripheral blood counts had returned to normal. and hematuria recurred. within 3 Examination was except for a febrile reaction of lOlF. hn.·entn.~n data included a hematocrit of 33 per of 4,300, BUN of 70 mg. per cent and of 3,9 mg. per cent. Sodium was 134 mEq. per L, chloride 102 mEq. per L, carbon dioxide 19 mEq. per Land potassium 4.4 mEq. per L. Chest x-ray and electrocardiogram showed no acute changes. Urinary output for the 24 hours after hospitalization was 1,700 ml. IVP showed

FIG. 3. Narrowed and thickened distal ureter (arrow) entering contracted bladder.

delayed function and dilation of the right caliceal system (fig. 2, A). revealed severe bladder and a patulous right ureteral orifice. A right retrograde pyelogram demonstrated a narrow and irregular ureter with proximal pelviocalicea! dilation 2, B). Resistance was encountered in a No. 5 catheter through the distal ureter but the catheter was successfully positioned in the renal pelvis. Respiratory distress developed and arterial blood gas studies (4 L oxygen) revealed an oxygen pressure of 235 mm. Hg, carbon dioxide pressure of 50 mm. Hg and pH equal to 7.11. Despite intravenous sodium bicarbonate and respiratory assistance the patient died 18 hours after catheter placement with a pre-termi-

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FIG. 4. Severe hydropic degeneration of renal collecting tubules. Reduced from x 160

nal pH recorded at 7 .09. Hypotension did not occur and urinary output continued to be 50 ml. per hour (specific gravity equal to 1.015) until death. At autopsy the pelviocaliceal system and proximal ureter were dilated. The distal and intravesical ureter were narrowed and thickened and the bladder was contracted and fibrotic (fig. 3). Microscopic examination of the ureter and bladder revealed chronic and acute inflammatory reaction in the mucosa with fibrotic changes in the ureteral and vesical musculature. Severe hydropic degeneration was evident in the collecting tubules (fig. 4). No area of transitional cell malignancy was identified. Microscopic examination of the bone marrow was normal. DISCUSSION

The alkalating agent thio-tepa has been used as a mode of topical chemotherapy for non-invasive vesical malignancy. Veenema and associates found that complete or partial destruction of stage O and stage A transitional cell carcinoma is achieved in two-thirds of the patients so treated. 5 Investigators have suggested using thio-tepa not only for the destruction of existing papillary lesions but also as a means of prophylaxis in bladders with a demonstrated propensity for frequent multifocal recurrences. Dose regimens range from 30 to 60 mg., administered at weekly intervals for 4 to 6 weeks. Thio-tepa is absorbed through the vesical mucosa by simple diffusion. Jones and Swinney found that a third of the amount instilled in the bladder will be systemically absorbed during a 3-hour period. 4 Lunglmayr and Czech demonstrated that the amount of thio-tepa absorbed varied widely according to the condition of the vesical mucosa. 5 Veenema, R. J., Dean, A. L., Jr., Uson, A. C., Roberts, M. and Longo, F.: Thiotepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. Urol., 101: 711, 1969.

An inflamed mucosa will allow passage of more than 50 per cent of an administered dose during a 1-hour period. 6 A toxic manifestation of thio-tepa is suppression of the hematopoietic system which may be precipitous and unpredictable. Vesicoureteral reflux, which increases the surface area exposed to thio- tepa, will enhance absorption and mcrease the likelihood of hematopoietic suppression. 7 Local side effects associated with the use of thio-tepa include lower abdominal pain, vesical irritability and hematuria. These symptoms have reversed with discontinuation of the drug. Our patient manifested severe vesical reaction to thiotepa. In addition the distal ureter was fibrotic and narrowed. Distortion of the ureterovesical junction may have permitted reflux of thio-tepa into the right ureter precipitating ureteritis. Partial ureteral obstruction and compromise of renal function in the solitary kidney resulted. Since these changes appeared during the course of thio-tepa therapy, thio-tepa was thought to be responsible. In addition to an obstructive cause for renal failure another mechanism is suggested. Extensive hydropic degeneration was present in the renal collecting tubules. The patient had received no diuretics or nephrotoxic drugs to account for these changes nor was he hypotensive or hypokalemic. Corriere and associates have shown that when radioactively-labeled particles are carried with refluxing urine to the renal pelvis they will not be mechanically eliminated with urinary drainage. 8 6 Lunglmayr, G. and Czech, K.: Absorption studies on intraluminal thio-tepa for topical cytostatic treatment of low-stage bladder tumors. J. Urol., 106: 72, 1971. 7 Orlin, I.: The role of cystography in thio-tepa toxicity. J. Urol., 108: 257, 1972. 'Corriere, J. N., Jr., Lipschutz, L. I., Judson, F. N. and Murphy, J. J .: Autoradiographic localization of refluxed live and dead Escherichia coli and sulfur colloid particles in the rat kidney. Invest. Urol., 6: 364, 1969.

RENAL FATLL~RE

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1.nedulla and cortex afte:t aL 1-:oer and rnay rernai:r1 up to 28 The intra,enal system has been identified as the avenue of parenchymal entrance. The tubular changes suggest exposure to a toxic substance and may be which refluxed and was lymphatics. It is noteworthy that studying excretion of thio-tepa, administered parenterally or intravenously for the treatment of other malignancies, have not recovered the drug or its metabolites in human urine. 9 'Mellett, L. B., Hodgson, P. E. and Woods, L. A.: Absorption and fate of C14-labeled N, N1, N 11 -trieth-

SLMMARY

A case is reported in which extensive local vesical reaction to thio-tepa resulted in ureteral obstruction and renal failure. This toxic effect of intravesicai thio-tepa has not been described. A possible mechanism for direct renal toxicity is presented. In addition to hematologic studies, monitoring of renal function pyelography and serum chemistry is warranted when intravesical thio-tepa is used. ------

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ylenethiophosphoramide (thio-tepa) in humans dogs. J. Lab. Clin. Med., 60: 818, 1962.

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