Intestinal Necrosis and Perforation After Renal Transplantation Robert H.
Demling, MD; Oscar Salvatierra, Jr., MD;
Folkert O.
Belzer,
An acute intestinal disorder occurred in seven patients soon after renal transplantation. The disorder was characterized initially by massive abdominal distention with progression to multiple bowel perforations in three patients and extensive bowel necrosis in two. Surgical manipulation did not appear to be the cause since the transplants were performed retroperitoneally in the iliac fossa. Ischemia also was not a factor since the mesenteric vessels were patent with no evidence of thrombus formation or vasculitis. The cause appeared to be related to immunosuppressive agents, in particular, high doses of corticosteroids. The disease process appeared to be reversible if immunosuppression was discontinued early, as occurred in two patients.
intestinal in of renal are not uncom¬ fatal.14 The lethal nature of these mon and are complications has been attributed to the inability of these patients to withstand severe infection. We are reporting on seven patients who developed acute intestinal compli¬ cations immediately after renal transplantation or in the early postoperative period. These events appear to be part of a distinct pathological entity occurring in renal homograft recipients. The disorder is characterized clinically by the sudden onset of severe abdominal distention followed by pain, with progression to intestinal perforation or ac¬ tual infarction. This disease state appears to be reversible if high doses of immunosuppressive agents are discontin¬ ued early in its course, as was seen in two of the patients (Table). Four of the more illuminating case histories are reviewed in detail.
immunosuppressed Majorrecipientsusuallycomplications homografts
REPORT OF CASES Case 1.—A 26-year old man underwent a second renal trans¬ plant from a cadaver donor after he had rejected his first trans¬ plant one year previously. The present homograft was placed in the left iliac fossa, and the patient was begun on immunosuppres¬ sive therapy consisting initially of 120 mg prednisone daily and 150 mg azathioprine (Imuran) daily. He required dialysis on the
Accepted
for
publication Sept 3, Surgery, University
MD
second postoperative day because of depressed renal function. Two days later he developed severe abdominal distention with some pain. Abdominal x-ray films showed a severe ileus pattern (Fig 1, left). His symptoms progressed and an exploratory lap¬ arotomy was performed. The bowel showed no signs of obstruc¬ tion or infarction, although small areas of transmural ileal dis¬ coloration were seen and the entire bowel was greatly distended. The bowel was decompressed and the abdomen was closed. He im¬ proved initially, but on the 11th postoperative day he again com¬ plained of severe abdominal pain. Reexploration showed perfora¬ tion of the ascending colon. The mesenteric vessels were patent. Azathioprine was discontinued and prednisone was reduced to 10 mg daily. His postoperative course was stormy, and he died 27 days after transplantation. Necropsy showed multiple perfora¬ tions of the large and small bowel with fistula formation. Large segments of bowel were completely necrotic. Submucosal vessels were patent as were the superior and inferior mesenteric vessels. There was no evidence of vasculitis or fibrin thrombi. Case 2.—A 30-year-old man received a cadaver renal homograft in the right iliac fossa. Initial immunosuppressive therapy con¬ sisted of 120 mg prednisone daily and 150 mg azathioprine daily. On the first postoperative day, severe abdominal distention and mild abdominal pain were noted (Fig 1, right). Hemodialysis was begun for persistent hyperkalemia. Twelve hours after dialysis, the patient's abdomen became rigid and his urinary output fell precipitously. Abdominal x-ray films showed intramural air in the Intestinal
of California Medical
Reprint requests Transplant Service, 884M, University fornia, San Francisco, CA 94143 (Dr. Salvatierra). to
Room
of Cali-
Renal
Transplantation
Patient
No./Age, yr/Sex 1/26/M 2/30/M
3/28/M 4/24/M 5/21/M
1974.
From the Department of School, San Francisco.
Complications After
6/28/M 7/42/M
Complication Extensive transmural of small and large Extensive transmural of small and large
necrosis bowel necrosis bowel Marked abdominal distention and abdominal pain Marked abdominal distention and abdominal pain Extensive necrosis of large bowel; mucosal ulcérations of small bowel Multiple perforations of ascending colon Perforation of descending colon
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
Onset After Trans-
Out-
plant
come
36 hr
Died
24 hr
Died
36 hr
Living
17 days
Living
2
mo
Died
2
mo
Living
2
mo_Died
Fig
1.—Distentions of
large and small bowel in patients 1 (left) and 2 (right). Both patients developed massive bowel necrosis and died.
Fig 2. Distention of large and small bowel in patients 3 vived after immunosuppression was discontinued.
(left) and 4 (right). Both patients responded
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
to conservative
management and
sur¬
large bowel.
A
laparotomy
revealed
an
infarction of the distal
part of the ileum and the entire colon. The mesenteric vessels were patent and pulsating. Immunosuppressive agents were dis¬
continued. The patient's condition deteriorated, and he died sev¬ eral days later. Necropsy showed multiple large and small bowel perforations with necrosis of large segments of bowel. Sub¬ mucosal vessels were patent, as were the mesenteric vessels. There was no evidence of vasculitis. Case 3.—A 28-year-old man received a kidney transplant in the left iliac fossa from a living related donor. Initial kidney function was good. Immunosuppression consisted of 120 mg prednisone and 150 mg azathioprine per day initially. Thirty-six hours after sur¬ gery he exhibited marked abdominal distention (Fig 2, left), de¬ creased bowel sounds, and progressive abdominal pain. Aza¬ thioprine was discontinued and prednisone decreased to 10 mg daily. He was treated with nasogastric suction, and the abdominal pain and distention subsided two days later. He had no further complications, and was discharged from the hospital with good function in his transplanted kidney. Case 4.—A 24-year-old man underwent a cadaver renal trans¬ plant to his right iliac fossa. Postoperative renal function was good. Initial immunosuppression was 120 mg prednisone and 150 mg azathioprine. On day 17, one day after drainage of a lymphocele in the wound, he developed marked abdominal distention, pain, and fever (Fig 2, right). The dose of prednisone was immedi¬ ately decreased from 80 mg to 20 mg and the azathioprine therapy was discontinued. He was treated with nasogastric suction with gradual improvement, and was discharged from the hospital with a
well-functioning kidney.
COMMENT
Major intestinal problems are not uncommon following renal transplantation. Penn et al1 reported on a variety of colon disorders occurring from eight days to over a year after transplantation. Hadjiyannakis et al- and Misra et al3 also reported on a variety of intestinal complications following transplantation of renal homografts. Powis et al4 reported on five renal homograft recipients with ileocolic perforation and necrosis occurring two weeks to V-k years after transplant. These lesions were believed to be secondary to ischemia, with thrombosis of small vessels found at necropsy. Vasculitis was described in some of the specimens. In 650 renal transplants at this center, seven patients developed an acute intestinal disorder in the early posttransplantation period. All seven patients were young men with no prior history of intestinal or vascular disease. Initial symptoms were abdominal distention and pain, progressing to bowel necrosis and, frequently, to death. Pathological findings ranged from isolated perforations of the bowel to areas of complete necrosis. There was no evi¬ dence of mesenteric vessel obstruction or thrombosis in¬ cluding submucosal vessels. No vasculitis was seen. Cases 3 and 4 are included in the series because the severe ab¬ dominal distention and pain in these patients was similar to that seen in the early course of the other patients and no other cause was evident. We perform renal transplantation retroperitoneally, in the iliac fossa, and do not enter the peritoneal cavity. The
surgical procedure therefore does not appear to be a cause of this complication. Although the clinical course of sev¬ eral patients was similar to that found in the series of coIonic perforations described by Powis et al, pathologic findings differed in that thrombosis of mesenteric vessels Ischemia, therefore, did
not appear to be a series. major etiological Immunosuppressive agents, corticosteroids in particu¬ lar, appear to be primary etiologic factors. Colonie perfo¬ rations secondary to long-term corticosteroid adminis¬ tration have been reported.77 Corticosteroids are known to directly affect connective tissue, impeding the reparative process and reducing the resistance of intestinal mucosa to bacteria and digestive juices." Azathioprine decreases the resistance to infection but, by itself, has not been known to produce actual bowel necrosis. Because of the complex nature of the body's response to these agents, their role in the production of this intestinal disorder re¬ mains unknown. Since this form of intestinal complication leading to actual bowel necrosis appears more common in transplant patients on immunosuppresive therapy than in nontransplant patients who are taking immunosuppres¬ sive drugs, the presence of foreign tissue may potentiate or actually initiate this disease state. The observation that all the patients were young men may be important in that half of the patients on our transplant service are male. This suggests that a hormonal factor may be involved. Because of the devastating nature of this complication when allowed to progress, we now discontinue immuno¬ suppresive agents if substantial bowel distention of un¬ known cause occurs after transplantation. Early discon¬ tinuation of these drugs in cases 3 and 4 seemed to reverse this process. Although this policy increases the risk of los¬ ing the homograft, therapy must be directed toward pa¬ tient survival. If the abdominal symptoms rapidly im¬ prove, immunosuppression may be cautiously resumed. was
not
seen.
factor in
This investigation was 11290 and GM-01474.
our
supported by
Public Health Service grants AM-
References 1. Penn I, Brettschneider L, Simpson K, et al: Major colonic problems in human homotransplant recipients. Arch Surg 100:61\x=req-\ 65, 1970. 2. Hadjiyannakis EJ, Evans DB, Smellie WAB, et al: Gastrointestinal complications after renal transplantation. Lancet 2:781\x=req-\ 785, 1971. 3. Misra MK, Pinkus GS, Birtch AG, et al: Major colonic diseases complicating renal transplantation. Surgery 73:942-948,
1973. 4. Powis SJA, Barnes AD, Dawson-Edwards P, et al: Ileocolonic problems after cadaveric renal transplantation. Br Med J 1:99\x=req-\ 101, 1972. 5. Fein BT: Perforation and inflammation of diverticula of the colon secondary to long-term adrenocorticosteroid therapy for bronchial asthma and pulmonary emphysema. South Med J 54:355\x=req-\ 365, 1954. 6. Sautter RD, Ziffren SE: Adrenocortical steroid therapy resulting in unusual gastrointestinal complications. Arch Surg 79:346-356, 1959.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
Demling, MD; Oscar Salvatierra, Jr., MD;
Folkert O.
Belzer,
An acute intestinal disorder occurred in seven patients soon after renal transplantation. The disorder was characterized initially by massive abdominal distention with progression to multiple bowel perforations in three patients and extensive bowel necrosis in two. Surgical manipulation did not appear to be the cause since the transplants were performed retroperitoneally in the iliac fossa. Ischemia also was not a factor since the mesenteric vessels were patent with no evidence of thrombus formation or vasculitis. The cause appeared to be related to immunosuppressive agents, in particular, high doses of corticosteroids. The disease process appeared to be reversible if immunosuppression was discontinued early, as occurred in two patients.
intestinal in of renal are not uncom¬ fatal.14 The lethal nature of these mon and are complications has been attributed to the inability of these patients to withstand severe infection. We are reporting on seven patients who developed acute intestinal compli¬ cations immediately after renal transplantation or in the early postoperative period. These events appear to be part of a distinct pathological entity occurring in renal homograft recipients. The disorder is characterized clinically by the sudden onset of severe abdominal distention followed by pain, with progression to intestinal perforation or ac¬ tual infarction. This disease state appears to be reversible if high doses of immunosuppressive agents are discontin¬ ued early in its course, as was seen in two of the patients (Table). Four of the more illuminating case histories are reviewed in detail.
immunosuppressed Majorrecipientsusuallycomplications homografts
REPORT OF CASES Case 1.—A 26-year old man underwent a second renal trans¬ plant from a cadaver donor after he had rejected his first trans¬ plant one year previously. The present homograft was placed in the left iliac fossa, and the patient was begun on immunosuppres¬ sive therapy consisting initially of 120 mg prednisone daily and 150 mg azathioprine (Imuran) daily. He required dialysis on the
Accepted
for
publication Sept 3, Surgery, University
MD
second postoperative day because of depressed renal function. Two days later he developed severe abdominal distention with some pain. Abdominal x-ray films showed a severe ileus pattern (Fig 1, left). His symptoms progressed and an exploratory lap¬ arotomy was performed. The bowel showed no signs of obstruc¬ tion or infarction, although small areas of transmural ileal dis¬ coloration were seen and the entire bowel was greatly distended. The bowel was decompressed and the abdomen was closed. He im¬ proved initially, but on the 11th postoperative day he again com¬ plained of severe abdominal pain. Reexploration showed perfora¬ tion of the ascending colon. The mesenteric vessels were patent. Azathioprine was discontinued and prednisone was reduced to 10 mg daily. His postoperative course was stormy, and he died 27 days after transplantation. Necropsy showed multiple perfora¬ tions of the large and small bowel with fistula formation. Large segments of bowel were completely necrotic. Submucosal vessels were patent as were the superior and inferior mesenteric vessels. There was no evidence of vasculitis or fibrin thrombi. Case 2.—A 30-year-old man received a cadaver renal homograft in the right iliac fossa. Initial immunosuppressive therapy con¬ sisted of 120 mg prednisone daily and 150 mg azathioprine daily. On the first postoperative day, severe abdominal distention and mild abdominal pain were noted (Fig 1, right). Hemodialysis was begun for persistent hyperkalemia. Twelve hours after dialysis, the patient's abdomen became rigid and his urinary output fell precipitously. Abdominal x-ray films showed intramural air in the Intestinal
of California Medical
Reprint requests Transplant Service, 884M, University fornia, San Francisco, CA 94143 (Dr. Salvatierra). to
Room
of Cali-
Renal
Transplantation
Patient
No./Age, yr/Sex 1/26/M 2/30/M
3/28/M 4/24/M 5/21/M
1974.
From the Department of School, San Francisco.
Complications After
6/28/M 7/42/M
Complication Extensive transmural of small and large Extensive transmural of small and large
necrosis bowel necrosis bowel Marked abdominal distention and abdominal pain Marked abdominal distention and abdominal pain Extensive necrosis of large bowel; mucosal ulcérations of small bowel Multiple perforations of ascending colon Perforation of descending colon
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
Onset After Trans-
Out-
plant
come
36 hr
Died
24 hr
Died
36 hr
Living
17 days
Living
2
mo
Died
2
mo
Living
2
mo_Died
Fig
1.—Distentions of
large and small bowel in patients 1 (left) and 2 (right). Both patients developed massive bowel necrosis and died.
Fig 2. Distention of large and small bowel in patients 3 vived after immunosuppression was discontinued.
(left) and 4 (right). Both patients responded
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
to conservative
management and
sur¬
large bowel.
A
laparotomy
revealed
an
infarction of the distal
part of the ileum and the entire colon. The mesenteric vessels were patent and pulsating. Immunosuppressive agents were dis¬
continued. The patient's condition deteriorated, and he died sev¬ eral days later. Necropsy showed multiple large and small bowel perforations with necrosis of large segments of bowel. Sub¬ mucosal vessels were patent, as were the mesenteric vessels. There was no evidence of vasculitis. Case 3.—A 28-year-old man received a kidney transplant in the left iliac fossa from a living related donor. Initial kidney function was good. Immunosuppression consisted of 120 mg prednisone and 150 mg azathioprine per day initially. Thirty-six hours after sur¬ gery he exhibited marked abdominal distention (Fig 2, left), de¬ creased bowel sounds, and progressive abdominal pain. Aza¬ thioprine was discontinued and prednisone decreased to 10 mg daily. He was treated with nasogastric suction, and the abdominal pain and distention subsided two days later. He had no further complications, and was discharged from the hospital with good function in his transplanted kidney. Case 4.—A 24-year-old man underwent a cadaver renal trans¬ plant to his right iliac fossa. Postoperative renal function was good. Initial immunosuppression was 120 mg prednisone and 150 mg azathioprine. On day 17, one day after drainage of a lymphocele in the wound, he developed marked abdominal distention, pain, and fever (Fig 2, right). The dose of prednisone was immedi¬ ately decreased from 80 mg to 20 mg and the azathioprine therapy was discontinued. He was treated with nasogastric suction with gradual improvement, and was discharged from the hospital with a
well-functioning kidney.
COMMENT
Major intestinal problems are not uncommon following renal transplantation. Penn et al1 reported on a variety of colon disorders occurring from eight days to over a year after transplantation. Hadjiyannakis et al- and Misra et al3 also reported on a variety of intestinal complications following transplantation of renal homografts. Powis et al4 reported on five renal homograft recipients with ileocolic perforation and necrosis occurring two weeks to V-k years after transplant. These lesions were believed to be secondary to ischemia, with thrombosis of small vessels found at necropsy. Vasculitis was described in some of the specimens. In 650 renal transplants at this center, seven patients developed an acute intestinal disorder in the early posttransplantation period. All seven patients were young men with no prior history of intestinal or vascular disease. Initial symptoms were abdominal distention and pain, progressing to bowel necrosis and, frequently, to death. Pathological findings ranged from isolated perforations of the bowel to areas of complete necrosis. There was no evi¬ dence of mesenteric vessel obstruction or thrombosis in¬ cluding submucosal vessels. No vasculitis was seen. Cases 3 and 4 are included in the series because the severe ab¬ dominal distention and pain in these patients was similar to that seen in the early course of the other patients and no other cause was evident. We perform renal transplantation retroperitoneally, in the iliac fossa, and do not enter the peritoneal cavity. The
surgical procedure therefore does not appear to be a cause of this complication. Although the clinical course of sev¬ eral patients was similar to that found in the series of coIonic perforations described by Powis et al, pathologic findings differed in that thrombosis of mesenteric vessels Ischemia, therefore, did
not appear to be a series. major etiological Immunosuppressive agents, corticosteroids in particu¬ lar, appear to be primary etiologic factors. Colonie perfo¬ rations secondary to long-term corticosteroid adminis¬ tration have been reported.77 Corticosteroids are known to directly affect connective tissue, impeding the reparative process and reducing the resistance of intestinal mucosa to bacteria and digestive juices." Azathioprine decreases the resistance to infection but, by itself, has not been known to produce actual bowel necrosis. Because of the complex nature of the body's response to these agents, their role in the production of this intestinal disorder re¬ mains unknown. Since this form of intestinal complication leading to actual bowel necrosis appears more common in transplant patients on immunosuppresive therapy than in nontransplant patients who are taking immunosuppres¬ sive drugs, the presence of foreign tissue may potentiate or actually initiate this disease state. The observation that all the patients were young men may be important in that half of the patients on our transplant service are male. This suggests that a hormonal factor may be involved. Because of the devastating nature of this complication when allowed to progress, we now discontinue immuno¬ suppresive agents if substantial bowel distention of un¬ known cause occurs after transplantation. Early discon¬ tinuation of these drugs in cases 3 and 4 seemed to reverse this process. Although this policy increases the risk of los¬ ing the homograft, therapy must be directed toward pa¬ tient survival. If the abdominal symptoms rapidly im¬ prove, immunosuppression may be cautiously resumed. was
not
seen.
factor in
This investigation was 11290 and GM-01474.
our
supported by
Public Health Service grants AM-
References 1. Penn I, Brettschneider L, Simpson K, et al: Major colonic problems in human homotransplant recipients. Arch Surg 100:61\x=req-\ 65, 1970. 2. Hadjiyannakis EJ, Evans DB, Smellie WAB, et al: Gastrointestinal complications after renal transplantation. Lancet 2:781\x=req-\ 785, 1971. 3. Misra MK, Pinkus GS, Birtch AG, et al: Major colonic diseases complicating renal transplantation. Surgery 73:942-948,
1973. 4. Powis SJA, Barnes AD, Dawson-Edwards P, et al: Ileocolonic problems after cadaveric renal transplantation. Br Med J 1:99\x=req-\ 101, 1972. 5. Fein BT: Perforation and inflammation of diverticula of the colon secondary to long-term adrenocorticosteroid therapy for bronchial asthma and pulmonary emphysema. South Med J 54:355\x=req-\ 365, 1954. 6. Sautter RD, Ziffren SE: Adrenocortical steroid therapy resulting in unusual gastrointestinal complications. Arch Surg 79:346-356, 1959.
Downloaded From: http://archsurg.jamanetwork.com/ by a New York University User on 06/21/2015
