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Ureteral obstruction after kidney transplantation secondary to bone metaplasia
CASE REPORTS
URETERAL OBSTRUCTION AFTER KIDNEY TRANSPLANTATION SECONDARY TO BONE METAPLASIA CESARE SELLI, ANDREA RISALITI, PIETRO DE ANTONI, UMBERTO MORO, ALFONSO CRISCI, AND CATHRYN ANNE SCOTT
ABSTRACT We report a case of ureteral obstruction after kidney transplantation caused by localized bone metaplasia in the donor ureter. Surgical treatment consisted of removal of the involved ureteral segment, which was located 3 cm above the bladder and creation of a spatulated end-to-end anastomosis. Although bone metaplasia has been observed in the ureteral wall of some animal species secondary to experimental ischemia and microtrauma, it is exceedingly rare in humans and has never before been documented after kidney transplantation. UROLOGY 56: 153iv–153vi, 2000. © 2000, Elsevier Science Inc.
U
reteral stenosis occurs in 3% to 8% of patients after kidney transplantation, and its etiology is not completely clear.1 It has been attributed to inadequate surgical technique, postischemic fibrosis, and vasculitis secondary to rejection episodes.2 The typical radiologic appearance is hydronephrosis, with tapering of the distal ureter. Ureteral stones are relatively uncommon after renal transplantation, and they can cause obstructive anuria in 0.5% of cases.3 Since transplant kidneys are denervated, no renal colic occurs, and obstruction in a transplant setting appears clinically as a decrease in renal function, demonstrated by elevation of serum creatinine and decreased urinary output. The diagnostic method more frequently used in this situation is pelvic ultrasound, although intravenous urography and percutaneous opacification can delineate the site of obstruction more precisely. We recently treated a patient with extrinsic obstruction of the transplanted ureter secondary to bony metaplasia. CASE REPORT A 27-year-old man, 1 year after an uneventful cadaver kidney transplantation, presented with From the Department of Surgical Sciences, Divisions of Urology and General Surgery, and Department of Pathology, University of Udine, Udine, Italy Address for correspondence: Cesare Selli, M.D., Clinica Urologica, Policlinico Universitario, I-33013 Gemona del Friuli, Udine, Italy Submitted: July 16, 1999, accepted (with revisions): January 20, 2000
153iv
© 2000, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
progressive decrease of renal function, with a serum creatinine level of 2 mg/dL. Pelvic ultrasound revealed dilation of the renal pelvis and upper ureter in the transplanted kidney. Intravenous urography revealed dilation of the renal pelvis and ureter, which ended abruptly near the bladder in the ovoid calcification located above the right ischiopubic branch that measured 1 ⫻ 2.5 cm (Fig. 1) as noted on the scout film. The calcification was tentatively considered a large ureteral stone (Fig. 2). Serum calcium and parathyroid hormone levels were within normal limits. Retrograde pyelography was attempted but failed, and ureteroscopy revealed an unsurpassable slit-like obstruction of the ureteral lumen at 3 cm from the bladder, which could not be negotiated with a hydrophilic guide wire. The mucosa of the obstructed area was yellowish. At surgery, a normal ureterovesical anastomosis was found. Above it was a hard mass 3 cm in diameter that was attached to the pelvic muscles and engulfed the ureter; the renal pelvis and the upper ureter appeared dilated. The mass was removed, together with the obstructed ureteral segment, and a spatulated endto-end ureteral anastomosis was performed over a 6F, double J stent 16 cm long. In the postoperative course, the serum creatinine level decreased to 1.4 mg/dL, and the double J stent was removed after 2 months. One year after the procedure, the patient had normal renal function. A control pelvic ultrasound scan and intravenous urography revealed no evidence of dilation or calcifications. Histopathologic examination revealed multiple 0090-4295/00/$20.00 PII S0090-4295(00)00490-8
FIGURE 1. Scout film of the pelvis revealing an ovoid calcification located above the right ischiopubic branch.
FIGURE 3. Photomicrograph (hematoxylin-eosin, original magnification ⫻3.2) showing a panoramic view of the ureteral wall, with disseminated foci of bone metaplasia within the tunica propria and muscularis. Transitional cell lining of the lumen is absent in this section. The inset (hematoxylin-eosin, original magnification ⫻20) reveals a focus of bone metaplasia surrounded by a rim of osteoblasts.
ated cells reactive to the CD68 KP1 antiserum, a marker of monocytic lineage, were also present. COMMENT
FIGURE 2. Intravenous urogram showing dilation of the pelvis and ureter in the transplanted kidney terminating abruptly near the bladder in the calcification noted on the scout film.
foci of heterotopic bony tissue, with chondroid areas within the ureteral wall, limited to the tunica propria and muscularis (Fig. 3). The mucosa was frequently devoid of a urothelial lining, which, where present, was mildly hyperplastic. The metaplastic foci were embedded in fibrous tissue, rich in activated fibroblasts, and frequently surrounded by a lymphoid and plasma cellular inflammatory infiltrate composed both of B cells (CD20, L26 reactive) and T cells (CD3⫹). The metaplastic foci were surrounded by a rim of mononucleated, vimentin-positive cells, with features of osteoblasts (Fig. 3). Furthermore, occasionally, multinucleUROLOGY 56 (1), 2000
During normal osteogenesis, the osteoclasts, cells of hemopoietic and monocytic lineage, resorb and invade the calcified cartilage rudiment; thus, the primitive marrow cavity is formed and hemopoiesis initiates. Osteogenic cells, osteoblasts and osteocytes, which derive from the multipotent mesenchymal stem cells, control the development and activity of the osteoclasts through the local release of factors such as granulocyte-macrophage colony-stimulating factor, macrophage colonystimulating factor, and interleukin-6.4 In heterotopic ossification (bone metaplasia), osteoclasts derive from mature local macrophages of monocytic origin, and vascular endothelium and pericytes are integrated in the nucleus of ossification and act as precursors of bone-forming cells.5 Bone metaplasia can be observed in various clinical conditions. Those relevant to the present case are two: secondary hyperparathyroidism associated with chronic renal insufficiency, of which the patient showed no evidence, and chronic inflammation. The latter, by means of the release of cytokines, growth factors (eg, platelet-derived growth factor, transforming growth factor-beta, fibroblast growth factor, epidermal growth factor), and complement, may induce the formation of metaplastic bone.6,7 Even though the urothelium is known to have osteoinductive properties in experimental animals, this is seldom seen in humans.8 In fact, although 153v
bone metaplasia has been reported to occur in the ureters of some animal species after experiments of ureteral regeneration and in autologous free ureteral grafts, secondary to ischemia and microtrauma,9 to the best of our knowledge, only 3 cases of ureteral bone metaplasia in humans have been reported. Only one of these cases had no history of previous injury.7–9 The most likely explanation for the presence of bone metaplasia within the ureteral wall in the present patient is ischemia, although during the transplant nothing unusual was noted concerning the donor ureter, and the procedure was performed in a standard fashion. The site of bone metaplasia was 3 cm above the suture line with the bladder, and early ischemia or direct trauma of the distal end of the donor ureter cannot be considered as the certain cause of the process. It is more likely that late ischemia developed, triggering chronic inflammation, and that the distal part of the ureter had already established vascularization from the recipient bladder. The time span for the clinical development of the obstruction was less than 1 year. This is in keeping with previous reports7–9 of ureteral bone metaplasia in humans and with the results of the culture of fresh marrow cells obtained from the femora of Fischer rats. In the latter, osteoblastic cells and microscopic mineralized nodules appeared about 1 week after the subculture, and many macroscopic nodules showed high alkaline phosphatase activity at 2 weeks.10 Our case appears to be the first reported, according to our review using the Medline data base, of any association between bone metaplasia and renal transplantation. Morphologically, differential diagnosis included idiopathic retroperitoneal fibrosis (Ormond’s disease), which, in analogy to fibro-
153vi
matoses in other sites, may show areas of bony metaplasia on occasion. This possibility was excluded because the cellular tissue surrounding the muscularis showed no evidence of fibrosis, and heterotopic bone was present only within the ureteral wall. Finally, ureteral obstruction radiologically and sonographically resembling a stone can actually represent an area of bone metaplasia within the ureteral wall and requires surgical treatment. REFERENCES 1. Collado A, Caparro`s J, Guirado L, et al: Balloon dilatation in the treatment of ureteral stenosis in kidney transplant recipients. Eur Urol 34: 399 – 403, 1998. 2. Streem SB, Novick AC, Steinmuller DR, et al: Long term efficacy of ureteral dilatation for transplant ureteral stenosis. J Urol 140: 32–35, 1998. 3. Lancina Martı`n JA, Garcı`a Buitro`n JM, Diaz Bermu`dez J, et al: Urinary lithiasis in transplanted kidney. Arch Esp Urol 50: 141–150, 1997. 4. Wlodarski K, Kuzaka B, Wlodarski P, et al: Is heterotopic bone formation occurring near a cut ureter a sign of osteo conductive potency of human urothelium? Urol Int 55: 115–117, 1995. 5. Blasco Casares FJ, Saladie´-Roig JM, Encabo-Mayoral R, et al: Histopathological and urographic findings in the autotransplanted ureter without kidney in dogs. Eur Urol 24: 291– 296, 1993. 6. Lindholm TS: Histodynamics of experimental heterotopic osteogenesis by transitional epithelium. Acta Chir Scand 39: 617– 623, 1973. 7. Klinger ME: Bone formation in the ureter: a case report. J Urol 75: 793, 1956. 8. Artmann M, and Eisasser E: Umschriebene Periureterale Verknocherung nach Operiert Retroperitonealer Ormond. Z Urol Nephrol 66: 211–214, 1973. 9. Rampal M, Pons G, Alimi JC, et al: Un cas d’ossification de l’urete`re. J Urol Nephrol 84: 265–270, 1978. 10. Ohgushi H, Dohi Y, Katuda T, et al: In vitro bone formation by rat marrow cell culture. J Biomed Mat Res 32: 333– 340, 1996.
UROLOGY 56 (1), 2000
URETERAL OBSTRUCTION AFTER KIDNEY TRANSPLANTATION SECONDARY TO BONE METAPLASIA CESARE SELLI, ANDREA RISALITI, PIETRO DE ANTONI, UMBERTO MORO, ALFONSO CRISCI, AND CATHRYN ANNE SCOTT
ABSTRACT We report a case of ureteral obstruction after kidney transplantation caused by localized bone metaplasia in the donor ureter. Surgical treatment consisted of removal of the involved ureteral segment, which was located 3 cm above the bladder and creation of a spatulated end-to-end anastomosis. Although bone metaplasia has been observed in the ureteral wall of some animal species secondary to experimental ischemia and microtrauma, it is exceedingly rare in humans and has never before been documented after kidney transplantation. UROLOGY 56: 153iv–153vi, 2000. © 2000, Elsevier Science Inc.
U
reteral stenosis occurs in 3% to 8% of patients after kidney transplantation, and its etiology is not completely clear.1 It has been attributed to inadequate surgical technique, postischemic fibrosis, and vasculitis secondary to rejection episodes.2 The typical radiologic appearance is hydronephrosis, with tapering of the distal ureter. Ureteral stones are relatively uncommon after renal transplantation, and they can cause obstructive anuria in 0.5% of cases.3 Since transplant kidneys are denervated, no renal colic occurs, and obstruction in a transplant setting appears clinically as a decrease in renal function, demonstrated by elevation of serum creatinine and decreased urinary output. The diagnostic method more frequently used in this situation is pelvic ultrasound, although intravenous urography and percutaneous opacification can delineate the site of obstruction more precisely. We recently treated a patient with extrinsic obstruction of the transplanted ureter secondary to bony metaplasia. CASE REPORT A 27-year-old man, 1 year after an uneventful cadaver kidney transplantation, presented with From the Department of Surgical Sciences, Divisions of Urology and General Surgery, and Department of Pathology, University of Udine, Udine, Italy Address for correspondence: Cesare Selli, M.D., Clinica Urologica, Policlinico Universitario, I-33013 Gemona del Friuli, Udine, Italy Submitted: July 16, 1999, accepted (with revisions): January 20, 2000
153iv
© 2000, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED
progressive decrease of renal function, with a serum creatinine level of 2 mg/dL. Pelvic ultrasound revealed dilation of the renal pelvis and upper ureter in the transplanted kidney. Intravenous urography revealed dilation of the renal pelvis and ureter, which ended abruptly near the bladder in the ovoid calcification located above the right ischiopubic branch that measured 1 ⫻ 2.5 cm (Fig. 1) as noted on the scout film. The calcification was tentatively considered a large ureteral stone (Fig. 2). Serum calcium and parathyroid hormone levels were within normal limits. Retrograde pyelography was attempted but failed, and ureteroscopy revealed an unsurpassable slit-like obstruction of the ureteral lumen at 3 cm from the bladder, which could not be negotiated with a hydrophilic guide wire. The mucosa of the obstructed area was yellowish. At surgery, a normal ureterovesical anastomosis was found. Above it was a hard mass 3 cm in diameter that was attached to the pelvic muscles and engulfed the ureter; the renal pelvis and the upper ureter appeared dilated. The mass was removed, together with the obstructed ureteral segment, and a spatulated endto-end ureteral anastomosis was performed over a 6F, double J stent 16 cm long. In the postoperative course, the serum creatinine level decreased to 1.4 mg/dL, and the double J stent was removed after 2 months. One year after the procedure, the patient had normal renal function. A control pelvic ultrasound scan and intravenous urography revealed no evidence of dilation or calcifications. Histopathologic examination revealed multiple 0090-4295/00/$20.00 PII S0090-4295(00)00490-8
FIGURE 1. Scout film of the pelvis revealing an ovoid calcification located above the right ischiopubic branch.
FIGURE 3. Photomicrograph (hematoxylin-eosin, original magnification ⫻3.2) showing a panoramic view of the ureteral wall, with disseminated foci of bone metaplasia within the tunica propria and muscularis. Transitional cell lining of the lumen is absent in this section. The inset (hematoxylin-eosin, original magnification ⫻20) reveals a focus of bone metaplasia surrounded by a rim of osteoblasts.
ated cells reactive to the CD68 KP1 antiserum, a marker of monocytic lineage, were also present. COMMENT
FIGURE 2. Intravenous urogram showing dilation of the pelvis and ureter in the transplanted kidney terminating abruptly near the bladder in the calcification noted on the scout film.
foci of heterotopic bony tissue, with chondroid areas within the ureteral wall, limited to the tunica propria and muscularis (Fig. 3). The mucosa was frequently devoid of a urothelial lining, which, where present, was mildly hyperplastic. The metaplastic foci were embedded in fibrous tissue, rich in activated fibroblasts, and frequently surrounded by a lymphoid and plasma cellular inflammatory infiltrate composed both of B cells (CD20, L26 reactive) and T cells (CD3⫹). The metaplastic foci were surrounded by a rim of mononucleated, vimentin-positive cells, with features of osteoblasts (Fig. 3). Furthermore, occasionally, multinucleUROLOGY 56 (1), 2000
During normal osteogenesis, the osteoclasts, cells of hemopoietic and monocytic lineage, resorb and invade the calcified cartilage rudiment; thus, the primitive marrow cavity is formed and hemopoiesis initiates. Osteogenic cells, osteoblasts and osteocytes, which derive from the multipotent mesenchymal stem cells, control the development and activity of the osteoclasts through the local release of factors such as granulocyte-macrophage colony-stimulating factor, macrophage colonystimulating factor, and interleukin-6.4 In heterotopic ossification (bone metaplasia), osteoclasts derive from mature local macrophages of monocytic origin, and vascular endothelium and pericytes are integrated in the nucleus of ossification and act as precursors of bone-forming cells.5 Bone metaplasia can be observed in various clinical conditions. Those relevant to the present case are two: secondary hyperparathyroidism associated with chronic renal insufficiency, of which the patient showed no evidence, and chronic inflammation. The latter, by means of the release of cytokines, growth factors (eg, platelet-derived growth factor, transforming growth factor-beta, fibroblast growth factor, epidermal growth factor), and complement, may induce the formation of metaplastic bone.6,7 Even though the urothelium is known to have osteoinductive properties in experimental animals, this is seldom seen in humans.8 In fact, although 153v
bone metaplasia has been reported to occur in the ureters of some animal species after experiments of ureteral regeneration and in autologous free ureteral grafts, secondary to ischemia and microtrauma,9 to the best of our knowledge, only 3 cases of ureteral bone metaplasia in humans have been reported. Only one of these cases had no history of previous injury.7–9 The most likely explanation for the presence of bone metaplasia within the ureteral wall in the present patient is ischemia, although during the transplant nothing unusual was noted concerning the donor ureter, and the procedure was performed in a standard fashion. The site of bone metaplasia was 3 cm above the suture line with the bladder, and early ischemia or direct trauma of the distal end of the donor ureter cannot be considered as the certain cause of the process. It is more likely that late ischemia developed, triggering chronic inflammation, and that the distal part of the ureter had already established vascularization from the recipient bladder. The time span for the clinical development of the obstruction was less than 1 year. This is in keeping with previous reports7–9 of ureteral bone metaplasia in humans and with the results of the culture of fresh marrow cells obtained from the femora of Fischer rats. In the latter, osteoblastic cells and microscopic mineralized nodules appeared about 1 week after the subculture, and many macroscopic nodules showed high alkaline phosphatase activity at 2 weeks.10 Our case appears to be the first reported, according to our review using the Medline data base, of any association between bone metaplasia and renal transplantation. Morphologically, differential diagnosis included idiopathic retroperitoneal fibrosis (Ormond’s disease), which, in analogy to fibro-
153vi
matoses in other sites, may show areas of bony metaplasia on occasion. This possibility was excluded because the cellular tissue surrounding the muscularis showed no evidence of fibrosis, and heterotopic bone was present only within the ureteral wall. Finally, ureteral obstruction radiologically and sonographically resembling a stone can actually represent an area of bone metaplasia within the ureteral wall and requires surgical treatment. REFERENCES 1. Collado A, Caparro`s J, Guirado L, et al: Balloon dilatation in the treatment of ureteral stenosis in kidney transplant recipients. Eur Urol 34: 399 – 403, 1998. 2. Streem SB, Novick AC, Steinmuller DR, et al: Long term efficacy of ureteral dilatation for transplant ureteral stenosis. J Urol 140: 32–35, 1998. 3. Lancina Martı`n JA, Garcı`a Buitro`n JM, Diaz Bermu`dez J, et al: Urinary lithiasis in transplanted kidney. Arch Esp Urol 50: 141–150, 1997. 4. Wlodarski K, Kuzaka B, Wlodarski P, et al: Is heterotopic bone formation occurring near a cut ureter a sign of osteo conductive potency of human urothelium? Urol Int 55: 115–117, 1995. 5. Blasco Casares FJ, Saladie´-Roig JM, Encabo-Mayoral R, et al: Histopathological and urographic findings in the autotransplanted ureter without kidney in dogs. Eur Urol 24: 291– 296, 1993. 6. Lindholm TS: Histodynamics of experimental heterotopic osteogenesis by transitional epithelium. Acta Chir Scand 39: 617– 623, 1973. 7. Klinger ME: Bone formation in the ureter: a case report. J Urol 75: 793, 1956. 8. Artmann M, and Eisasser E: Umschriebene Periureterale Verknocherung nach Operiert Retroperitonealer Ormond. Z Urol Nephrol 66: 211–214, 1973. 9. Rampal M, Pons G, Alimi JC, et al: Un cas d’ossification de l’urete`re. J Urol Nephrol 84: 265–270, 1978. 10. Ohgushi H, Dohi Y, Katuda T, et al: In vitro bone formation by rat marrow cell culture. J Biomed Mat Res 32: 333– 340, 1996.
UROLOGY 56 (1), 2000