Gastrointestinal
Hemorrhage Secondary to Cytomegalovirus
after Renal Transplantation A Case Report and Review of the Problem
Arnold G. Diethelm, MD, Birmingham, Alabama Ira Gore, MD, Birmingham, Alabama Lawrence T. Ch’ien, MD, Birmingham, Alabama William A. Sterling, MD, Birmingham, Alabama Jean M. Morgan, MD, Birmingham, Alabama
The syndrome of fever, anorexia, malaise, anemia, leukopenia, alterations in liver chemistries, and impaired renal function observed in patients after renal transplantation has been associated with elevated titers of complement-fixing antibodies to cytomegalovirus (CMV) [l-4]. Recognition of this viral infection in recipients of renal allografts was reported first by Rifkind and co-workers [5,6] followed by Hedley-Whyte and Craighead [7]. Cytomegalovirus also identified in the brain [I], lungs [1,8], liver [2,9,10], pancreas [1,9,11], adrenal [8,9], parathyroid, salivary glands, and kidney [1,8,12] leads to the conclusion that a high incidence [I4,7,13-191 of this virus occurred post transplantation in the immunosuppressed patient. Simultaneously, the frequency of this infection was noted in individuals chronically ill with debilitating diseases [20] or illnesses treated with steroids [9], radiation, and antimetabolites [20]. Gastrointestinal complications associated with CMV infection, although not common, have occurred primarily in the form of mucosal ulcerations in the esophagus [2], stomach [2,11], duodenum [ll], large [21-251 and small [II] intestine, and in the anal region [26]. The present report describes a patient who had massive and ultimately fatal upper gastrointestinal hemorrhage ten weeks post renal transplantation with CMV cultured first from the throat and later identified histologically in the gastric mucosa.
From the Departments of Surgery. Pathology, and Pediatrics, University of Alabama Medical Center and the Birmingham VA Hospital, University Station, Binninghem, Alabama. Reprint requests should be addressed to Arnold G. Diethelm. MD, Department of Surgery, University of Alabama Medical Center, University Station, Birmingham, Alabama 35294.
Vciuma 131, March 1976
Case Report The patient (#427-50-9668), a forty-five year old white male, was admitted to the Transplant Service after twenty-six months of chronic hemodialysis for end-stage renal disease secondary to chronic glomerulonephritis. Bilateral nephrectomy, performed one year earlier because of hypertension, restored blood pressure to within normal limits. The other significant feature of his medical history related to a gastroenterostomy and vagotomy for chronic duodenal ulcer disease with bleeding in 1963. On February 14,1973, the patient received a living related donor kidney from his mother (Terasaki D Match) with immediate renal function and a prompt diuresis, reducing the serum creatinine level to 1.8 mg/lOO ml on the third post-transplant day. (Figure 1.) Twentyone days later the blood urea nitrogen level was 23 mg/ 100 ml, serum creatinine level 1.8 mg/lOO ml, and creatinine clearance 50 ml/min. The patient felt well, was afebrile, and was discharged from the hospital to return daily for complete blood count, urinalysis, and blood urea nitrogen and serum creatinine determinations. Forty days after transplantation, renal function was stable with the patient receiving azathioprine 125 mg and prednisone 30 mg daily. On the forty-eighth postoperative day he experienced anorexia, fever, and leukopenia with a normal peripheral blood smear. The serum creatinine level increased to 2.9 mg/lOO ml with a decrease in the creatinine clearance. The kidney was increased in size and moderately tender on palpation. A diagnosis of acute rejection was established by clinical criteria, and the patient was readmitted to the hospital. Prednisone, increased to 300 mg/ay for two days, was gradually reduced to 50 mglday during the next two weeks. In addition, intravenous methylprednisolone (500 mg) was administered every three days for a total of six treatments with four treatments of radiation therapy (150 r to the midplane of the kidney). The dosage of azathioprine remained constant at 125 mg/day. During the next fourteen days (48 to 62 days post transplantation) the leukopenia (white blood count, 0.8 to 1.4) and fever of 100 to 102.6”F persisted. Because of the profound leukopenia,
371
Diethelm et al Cytomegalovirus was isolated from the throat by culture but not from the urine or peripheral blood leukocytes by technics previously described [27]. All cultures were negative for herpes simplex virus. Pathology
Prednlsone.
Day of TX
DAYS
mq/doy
POST-TRANSPLANTATION
Figure 1. in the presence of an apparently uncompiicated post-transplant course, the patient developed fever, ieukopenia, and impaired renal function simulating aiiografl rejection. Treatment with increased dosage of prednisone and x-ray therapy was unsuccessful in improving renal function. Hemorrhage of the upper gastrointestinal tract occurred on the sixty-eighth posttransplant day, requiring a subtotal gastrectomy for conhoi on the seventy-sixth day. 7be patient expired in renal failure with continued bleeding from the gastric remnant.
azathioprine was reduced to 50 mg every third day. The serum creatinine and blood urea nitrogen levels increased to 3.9 mg/lOO ml and 76 mg/lOO ml, respectively, with a decline in creatinine clearance to 17 ml/min. Because of impaired renal function and uremia, hemodialysis became necessary every other day. Despite a further decrease in creatinine clearance to 5 ml/min, the patient continued to produce a urine volume between 400 and 2,000 ml/24 hours. Sixty-eight days post transplantation an episode of upper gastrointestinal bleeding occurred. A barium contrast study of the upper gastrointestinal tract failed to demonstrate gastroduodenal or marginal ulceration, and gastroscopy revealed hemorrhagic gastritis. There was no clinical or laboratory evidence of abnormal clotting factors. Temperature elevations persisted (100 to 102’F), and although blood cultures for bacteria were repeatedly negative, the patient was started on penicillin, chloramphenicol, and gentamicin. Persistent bleeding from the upper gastrointestinal tract necessitated daily transfusions of leukocytefree packed red blood cells, and repeat gastroscopy showed multiple superficial ulcerations in the gastric mucosa with active bleeding. Because of continued blood loss, the patient underwent exploratory laparotomy, dismantling of the previous gastroenterostomy, and an 85 per cent subtotal gastric resection. During the next six days, bleeding continued from the gastric remnant, although the volume of blood loss was much less than that which occurred prior to gastrectomy. The patient expired eighty-two days after transplantation, maintaining a daily urine volume of 500 to 1,000 ml until death but requiring hemodialysis every other day.
372
The surgically resected segment of stomach terminating at the pylorus, measured 15.5 cm in length. Multiple superficial punctate bleeding ulcers 2 to 4 mm in size involved the mucosa of the lesser curvature in its proximal third. These were relatively distant from the stoma of the previous gastroenterostomy. Microscopically, all of the mucosal ulcerations extended to but not beyond the muscularis mucosae. In some, the ulcer bed consisted of a thin layer of granulation tissue. Others more acute displayed only a thin layer of fibrin without cellular infiltration covering the muscularis mucosae. Within the vicinity of the ulcers and extending from them, the deep lying gastric mucosal glands contained multiple scattered enlarged cells bearing conspicuous large blue-red intranuclear inclusions characteristic of CMV infection. (Figure 2.) The parasitized cells were entirely of the chief cell variety, including some in situ and others exfoliated into the tubular lumen. Remarkably little inflammation was associated with the presence of CMV-infected cells, even though there was disruption of the gastric tubules surrounded by a mild lymphocyte infiltration. No inclusion bodies were observed in the gastroenterostomy stoma or in the granulation tissue and endothelial cells of the ulcer beds. At autopsy, three days postoperatively, the gastric remnant still displayed evidence of CMV infection as noted above. The transplanted kidney was the seat of a severe suppurative pyelonephritis, the origin of an Escherichia coli septicemia. There was little evidence of acute or chronic rejection and no obstruction at the ureterovesical anastomosis. None of the organs other than the gastric mucosa contained CMV inclusions.
Comments
Involvement of the gastric mucosa with CMV was reported by Rosen and Hajdu [8,11] who observed cytomegalic inclusion bodies in the epithelium at the margins of gastric or duodenal ulcers in patients with Hodgkin’s disease, reticulum cell sarcoma, and leukemia. Millard et al [2] noted that three of twenty-five patients who died after renal transplantation had cytomegalic inclusion bodies
The American Journal of Surgery
Cytomegalovirus after Renal Transplantation
in the gastric mucosa with the appearance
of hem-
orrhagic gastritis and superficial erosion. Inciusion bodies, found within endothelial cells and in the glandular epithelium of the stomach, have been also reported by Wong and Warner [20] who observed inclusion bodies within endothelial cells and macrophages near sites of inflammation. The question as to whether or not the virus caused the mucosal ulceration or localized there at a later time cannot be answered. The source of the infection may be introduced by the allograft itself, transmitted by blood transfusions, or the reactivation of a latent infection secondary to the immunosuppressive therapy. Prince et al [29] noted a more than two-fold increase in the incidence of CMV infection when multiple transfusions were administered, which may be a significant factor in the case reported here. This patient had a number of transfusions administered first in 1963 for a bleeding duodenal ulcer and again during the year before transplantation while on dialysis all of which are a possible source of viral infection. Nagington [27] has shown by serologic studies that CMV infection is a common pathogen in transplant patients and may well be the result of reactivation of the virus. Upper gastrointestinal hemorrhage in patients after renal transplantation requires aggressive diagnosis and management since this complication has a high degree of morbidity and mortality. Gastroduodenal ulceration in such circumstances is the most common bleeding site and is often related to the use of corticosteroids. In our patient both gastroscopy and roentgenographic examination of the stomach failed to reveal evidence of gastroduodenal ulceration. Persistent bleeding, thought to be the result of hemorrhagic gastritis, prompted a second endoscopic study which then identified multiple gastric ulcerations. At surgery only small diffuse superficial ulcerations were noted without a specific identifiable bleeding point, and a high subtotal gastric resection was performed. Microscopic examination of the resected specimen of stomach revealed disruption of mucosal glands through exfoliation of parasitized epithelial cells. Cytomegalic inclusion bodies were identified in the ulcer margins and later at autopsy in the remaining portion of the gastric remnant. Although administration of antiviral agents such as adenine arabinoside to patients with the clinical syndrome of CMV have achieved a reduction of demonstrable titers in the urine and leukocytes [27], there is no evidence to date that such a chemotherapeutic approach would be of value in the treatment of pa-
vollmm 131, wrch 1978
Figure 2. Bofh the resected stomach and fhe gastrk remnant showed multlpie superficial ukeratkns containing lncluskn bodles in the gas&k mucosal glands character/&k of CMV Infection. 7’he parasitized ceils were of the chief cell variety and occurred both in situ and exfoliated into the tubular lumen.
tients with mucosai ulceration of the gastrointestinal tract. The association of impaired renal function in patients with cytomegaloviremia raises the question as to the possible role of the virus in precipitating allograft rejection. Support for this concept can be found in those patients with the clinical syndrome of CMV and impaired renal function who demonstrate classic histologic evidence of allograft rejection reversed by treatment with corticosteroids [3]. The previous histologic identification or recovery of the virus from the renal parenchyma [2,16,17,19] provides additional information that impaired renal function during episodes of viremia may be the result of either direct renal injury or graft rejection precipitated by the virus. The frequency of viruria, far moie common than microscopic identification of the virus in the kidney, suggests that impaired renal function may not be the result of the infection. The minimal amount of mononuclear cell infiltration, the moderate degree of renal enlargemelit, and the persistent urine volume of 500 to 1,000 ml/24 hours noted in the renal allograft in this patient mitigate against the usual clinical pattern of acute rejection. Although pyelonephritis may have contributed to the impaired renal function, it alone would not produce such a clinical syndrome. Altered renal function preceded by several days of fever and leukopenia, a common finding in those patients with nonfatal CMV infection, was clearly evident in our patient. Thus, an explanation for the decreasing renal
373
Diethelm
et al
function is not available solely on the basis of allograft rejection and suggests a direct involvement of the virus with the kidney parenchyma. Hepatic involvement secondary to CMV associated with an elevation of both serum glutamic oxalacetic transaminase and bilirubin levels and a decrease in serum albumin level has been recorded with varying frequency [2,9,10]. Microscopic examination of the liver in these circumstances has been reported to show normal architecture with areas of focal necrosis and mononuclear cell infiltration [2,10]. The profound decrease in serum albumin level noted in this patient and others in our experience has a serious prognosis even though the histologic appearance of the liver failed to demonstrate significant pathology. The comments by Rifkind [4] in 1965 seem most appropriate regarding CMV in renal allograft recipients and to this patient in particular. He noted that adequate explanations are not at hand for certain episodes of fever, pneumonia, gastrointestinal bleeding and hemorrhagic diatheses, hepatosplenomegaly, renal function impairment, and mental alterations, which have occurred after renal transplantation. His suggestion that some of these may be related to CMV infection has been supported by the present case in which many of these events were present including massive and fatal gastric hemorrhage with CMV present in the mucosa of both the resected stomach and the gastric remnant. Summary Generalized cytomegalovirus infection was associated with massive and ultimately fatal upper gastrointestinal bleeding in a renal allograft recipient and persisted even after subtotal gastric resection. The surgical specimen and the remaining stomach at autonsv revealed multinle suuerficial ulcerations with cytomegalic inclusion bodies within the gastric mucosa. Renal failure in the terminal stages of the patient’s illness required hemodialysis but did not seem to be the sole result of allograft rejection, suggesting that the renal dysfunction may be caused by the systemic viral infection. L
I
r
--A~
~~
References 1. Fine RN, Grushkin CM, Malekzadeh M, Wright HT: Cytomegalovirus syndrome following renal transplantation. Arch Surg 105: 564, 1972. 2. Millard PR. Herbertson BM, Nagington J, Evans DB: The morphological consequences and the significance of cytomegalovirus infection in renal transplant patients. Q J Med 42: 585, 1973.
374
3. Lopez C, Simmons RL, Mauer SM. Najarian JS, Good RA: Association of renal allograft rejection with virus infections. Am J Med 56: 280, 1974. 4. Rifkind D: Cvtomeaalovirus infection after renal transolantation. Archlnter~bd 116: 554. 1965. 5. Rifkind D, Starzl TE, Marchioro TL, Waddell WR, Rowlands DT, Hill RB: Transplantation pneumonia. JAMA 189: 808, 1964. 6. Hill RB, Rowlands DT, Rifkind D: Infectious pulmonary disease in patients receiving immunosuppressive therapy for organ transplantation. N Engl J Med 271: 1021, 1964. 7. Hedley-Whyte ET, Craighead JE: Generalized cytomegalic inclusion disease after renal homotransplantation. N Engl J Med 272: 473, 1965. 8. Rosen P, Hajdu S: Cytomegalovirus inclusion disease at autopsy of patients with cancer. Am J C/in Pathol 55: 749. 1971. 9. Evans DJ, Williams ED: Cytomegalic inclusion disease in the adult. J C/in Pathol27: 311, 1968. 10. Toghill PJ. Bailey ME, Williams R. Zeegen R, Brown R: Cytomegalovirus hepatitis in the adult. Lancet 1: 1351, 1967. 11. Rosen P, Armstrong D, Rice N: Gastrointestinal cytomegalovirus infection. Arch Intern Med 132: 274. 1973. 12. Simmons RL, Weil R Ill, Tallent MB, Kjellstrand CM, Najarian JS: Do mild infections trigger the rejection of renal allografts? Trans Proc 2: 419, 1970. 13. Anderson HK. Spencer ES: Cytomegalovirus infection among renal allograft recipients. Acta Medka Scandinavia 186: 7, 1969. 14. Balakrishnan SL, Armstrong D, Rubin AL, Stenzel KH: Cytomegalovirus infection after renal transplantation. JAMA 207: 1712, 1969. 15. Craighead JE: Immunologic response to cytomegalovirus infection in renal allograft recipients. Am J Epidemiol 90: 506, 1969. 16. Craighead JE: Pulmonary cytomegalovirus infection in the adult. Am J Pathol63: 487, 1971. 17. Craighead JE, Hanshaw JB, Carpenter CB: Cytomegalovirus infection after renal allotransplantation. JAMA 201: 725, 1967. 18. Henson D: Cytomegalovirus inclusion bodies in the gastrointestinal tract. Arch Pathol93: 477, 1972. 19. Rifkind D, Goodman N, Hill RB: The clinical significance of cytomegalovirus infection in renal transplant recipients. Ann In&n Med S$: 1116, 1967. 20. Wong T, Warner NE: Cytomegalic inclusion disease in adults. Arch Pathol74: 403. 1962. 21. Goodman MD, Porter DD: Cytomegalovirus vasculitis with fatal colonic hemorrhage. Arch Pathol96: 281, 1973. 22. Levine RS, Warner NE, Johnson CF: Cytomegalic inclusion disease in the oastrointestinal tract of adults. Ann Sure 159: 37, 1964. ” 23. Powell RP, Warner NE, Levine RS, Kirsner JB: Cytomegalic inclusion disease and ulceratic colitis. Am J Med 30: 334, 1961. 24. Tamura H: Acute ulcerative colitis associated with cytomegalic inclusion virus. Arch Pathol96: 164, 1973. 25. Wolfe BM, Cherry JD: Hemorrhage from cecal ulcers of cytomegalovirus infection: report of a case. Ann Surg 177: 490. 1973. 26. Nakoneczna I, Kay S: Fatal disseminated cytomegalic inclusion disease in an adult presenting with a lesion of the gastrointestinal tract. Am J Clin Pathol47: 124. 1967. 27. Nagington J: Cytomegalovirus antibody production in renal transplant patients. J Hyg 69: 645, 1971. 28. Ch’ien LT. Cannon NJ, Whitley RJ, Diethelm AG, Dismukes WE, Scott CW, Buchanan RA, Alford CA: Effect of adenine arabinoside on cytomegalovirus infections. J infect Dis 130: 32, 1974. 29. Prince AM, Szmuness W, Millian SJ, David DS: A serologic study of cytomegalovirus infections associated with blood transfusions. N Engl J Med 284: 1125, 1971.
The American Journal of Surgery
Hemorrhage Secondary to Cytomegalovirus
after Renal Transplantation A Case Report and Review of the Problem
Arnold G. Diethelm, MD, Birmingham, Alabama Ira Gore, MD, Birmingham, Alabama Lawrence T. Ch’ien, MD, Birmingham, Alabama William A. Sterling, MD, Birmingham, Alabama Jean M. Morgan, MD, Birmingham, Alabama
The syndrome of fever, anorexia, malaise, anemia, leukopenia, alterations in liver chemistries, and impaired renal function observed in patients after renal transplantation has been associated with elevated titers of complement-fixing antibodies to cytomegalovirus (CMV) [l-4]. Recognition of this viral infection in recipients of renal allografts was reported first by Rifkind and co-workers [5,6] followed by Hedley-Whyte and Craighead [7]. Cytomegalovirus also identified in the brain [I], lungs [1,8], liver [2,9,10], pancreas [1,9,11], adrenal [8,9], parathyroid, salivary glands, and kidney [1,8,12] leads to the conclusion that a high incidence [I4,7,13-191 of this virus occurred post transplantation in the immunosuppressed patient. Simultaneously, the frequency of this infection was noted in individuals chronically ill with debilitating diseases [20] or illnesses treated with steroids [9], radiation, and antimetabolites [20]. Gastrointestinal complications associated with CMV infection, although not common, have occurred primarily in the form of mucosal ulcerations in the esophagus [2], stomach [2,11], duodenum [ll], large [21-251 and small [II] intestine, and in the anal region [26]. The present report describes a patient who had massive and ultimately fatal upper gastrointestinal hemorrhage ten weeks post renal transplantation with CMV cultured first from the throat and later identified histologically in the gastric mucosa.
From the Departments of Surgery. Pathology, and Pediatrics, University of Alabama Medical Center and the Birmingham VA Hospital, University Station, Binninghem, Alabama. Reprint requests should be addressed to Arnold G. Diethelm. MD, Department of Surgery, University of Alabama Medical Center, University Station, Birmingham, Alabama 35294.
Vciuma 131, March 1976
Case Report The patient (#427-50-9668), a forty-five year old white male, was admitted to the Transplant Service after twenty-six months of chronic hemodialysis for end-stage renal disease secondary to chronic glomerulonephritis. Bilateral nephrectomy, performed one year earlier because of hypertension, restored blood pressure to within normal limits. The other significant feature of his medical history related to a gastroenterostomy and vagotomy for chronic duodenal ulcer disease with bleeding in 1963. On February 14,1973, the patient received a living related donor kidney from his mother (Terasaki D Match) with immediate renal function and a prompt diuresis, reducing the serum creatinine level to 1.8 mg/lOO ml on the third post-transplant day. (Figure 1.) Twentyone days later the blood urea nitrogen level was 23 mg/ 100 ml, serum creatinine level 1.8 mg/lOO ml, and creatinine clearance 50 ml/min. The patient felt well, was afebrile, and was discharged from the hospital to return daily for complete blood count, urinalysis, and blood urea nitrogen and serum creatinine determinations. Forty days after transplantation, renal function was stable with the patient receiving azathioprine 125 mg and prednisone 30 mg daily. On the forty-eighth postoperative day he experienced anorexia, fever, and leukopenia with a normal peripheral blood smear. The serum creatinine level increased to 2.9 mg/lOO ml with a decrease in the creatinine clearance. The kidney was increased in size and moderately tender on palpation. A diagnosis of acute rejection was established by clinical criteria, and the patient was readmitted to the hospital. Prednisone, increased to 300 mg/ay for two days, was gradually reduced to 50 mglday during the next two weeks. In addition, intravenous methylprednisolone (500 mg) was administered every three days for a total of six treatments with four treatments of radiation therapy (150 r to the midplane of the kidney). The dosage of azathioprine remained constant at 125 mg/day. During the next fourteen days (48 to 62 days post transplantation) the leukopenia (white blood count, 0.8 to 1.4) and fever of 100 to 102.6”F persisted. Because of the profound leukopenia,
371
Diethelm et al Cytomegalovirus was isolated from the throat by culture but not from the urine or peripheral blood leukocytes by technics previously described [27]. All cultures were negative for herpes simplex virus. Pathology
Prednlsone.
Day of TX
DAYS
mq/doy
POST-TRANSPLANTATION
Figure 1. in the presence of an apparently uncompiicated post-transplant course, the patient developed fever, ieukopenia, and impaired renal function simulating aiiografl rejection. Treatment with increased dosage of prednisone and x-ray therapy was unsuccessful in improving renal function. Hemorrhage of the upper gastrointestinal tract occurred on the sixty-eighth posttransplant day, requiring a subtotal gastrectomy for conhoi on the seventy-sixth day. 7be patient expired in renal failure with continued bleeding from the gastric remnant.
azathioprine was reduced to 50 mg every third day. The serum creatinine and blood urea nitrogen levels increased to 3.9 mg/lOO ml and 76 mg/lOO ml, respectively, with a decline in creatinine clearance to 17 ml/min. Because of impaired renal function and uremia, hemodialysis became necessary every other day. Despite a further decrease in creatinine clearance to 5 ml/min, the patient continued to produce a urine volume between 400 and 2,000 ml/24 hours. Sixty-eight days post transplantation an episode of upper gastrointestinal bleeding occurred. A barium contrast study of the upper gastrointestinal tract failed to demonstrate gastroduodenal or marginal ulceration, and gastroscopy revealed hemorrhagic gastritis. There was no clinical or laboratory evidence of abnormal clotting factors. Temperature elevations persisted (100 to 102’F), and although blood cultures for bacteria were repeatedly negative, the patient was started on penicillin, chloramphenicol, and gentamicin. Persistent bleeding from the upper gastrointestinal tract necessitated daily transfusions of leukocytefree packed red blood cells, and repeat gastroscopy showed multiple superficial ulcerations in the gastric mucosa with active bleeding. Because of continued blood loss, the patient underwent exploratory laparotomy, dismantling of the previous gastroenterostomy, and an 85 per cent subtotal gastric resection. During the next six days, bleeding continued from the gastric remnant, although the volume of blood loss was much less than that which occurred prior to gastrectomy. The patient expired eighty-two days after transplantation, maintaining a daily urine volume of 500 to 1,000 ml until death but requiring hemodialysis every other day.
372
The surgically resected segment of stomach terminating at the pylorus, measured 15.5 cm in length. Multiple superficial punctate bleeding ulcers 2 to 4 mm in size involved the mucosa of the lesser curvature in its proximal third. These were relatively distant from the stoma of the previous gastroenterostomy. Microscopically, all of the mucosal ulcerations extended to but not beyond the muscularis mucosae. In some, the ulcer bed consisted of a thin layer of granulation tissue. Others more acute displayed only a thin layer of fibrin without cellular infiltration covering the muscularis mucosae. Within the vicinity of the ulcers and extending from them, the deep lying gastric mucosal glands contained multiple scattered enlarged cells bearing conspicuous large blue-red intranuclear inclusions characteristic of CMV infection. (Figure 2.) The parasitized cells were entirely of the chief cell variety, including some in situ and others exfoliated into the tubular lumen. Remarkably little inflammation was associated with the presence of CMV-infected cells, even though there was disruption of the gastric tubules surrounded by a mild lymphocyte infiltration. No inclusion bodies were observed in the gastroenterostomy stoma or in the granulation tissue and endothelial cells of the ulcer beds. At autopsy, three days postoperatively, the gastric remnant still displayed evidence of CMV infection as noted above. The transplanted kidney was the seat of a severe suppurative pyelonephritis, the origin of an Escherichia coli septicemia. There was little evidence of acute or chronic rejection and no obstruction at the ureterovesical anastomosis. None of the organs other than the gastric mucosa contained CMV inclusions.
Comments
Involvement of the gastric mucosa with CMV was reported by Rosen and Hajdu [8,11] who observed cytomegalic inclusion bodies in the epithelium at the margins of gastric or duodenal ulcers in patients with Hodgkin’s disease, reticulum cell sarcoma, and leukemia. Millard et al [2] noted that three of twenty-five patients who died after renal transplantation had cytomegalic inclusion bodies
The American Journal of Surgery
Cytomegalovirus after Renal Transplantation
in the gastric mucosa with the appearance
of hem-
orrhagic gastritis and superficial erosion. Inciusion bodies, found within endothelial cells and in the glandular epithelium of the stomach, have been also reported by Wong and Warner [20] who observed inclusion bodies within endothelial cells and macrophages near sites of inflammation. The question as to whether or not the virus caused the mucosal ulceration or localized there at a later time cannot be answered. The source of the infection may be introduced by the allograft itself, transmitted by blood transfusions, or the reactivation of a latent infection secondary to the immunosuppressive therapy. Prince et al [29] noted a more than two-fold increase in the incidence of CMV infection when multiple transfusions were administered, which may be a significant factor in the case reported here. This patient had a number of transfusions administered first in 1963 for a bleeding duodenal ulcer and again during the year before transplantation while on dialysis all of which are a possible source of viral infection. Nagington [27] has shown by serologic studies that CMV infection is a common pathogen in transplant patients and may well be the result of reactivation of the virus. Upper gastrointestinal hemorrhage in patients after renal transplantation requires aggressive diagnosis and management since this complication has a high degree of morbidity and mortality. Gastroduodenal ulceration in such circumstances is the most common bleeding site and is often related to the use of corticosteroids. In our patient both gastroscopy and roentgenographic examination of the stomach failed to reveal evidence of gastroduodenal ulceration. Persistent bleeding, thought to be the result of hemorrhagic gastritis, prompted a second endoscopic study which then identified multiple gastric ulcerations. At surgery only small diffuse superficial ulcerations were noted without a specific identifiable bleeding point, and a high subtotal gastric resection was performed. Microscopic examination of the resected specimen of stomach revealed disruption of mucosal glands through exfoliation of parasitized epithelial cells. Cytomegalic inclusion bodies were identified in the ulcer margins and later at autopsy in the remaining portion of the gastric remnant. Although administration of antiviral agents such as adenine arabinoside to patients with the clinical syndrome of CMV have achieved a reduction of demonstrable titers in the urine and leukocytes [27], there is no evidence to date that such a chemotherapeutic approach would be of value in the treatment of pa-
vollmm 131, wrch 1978
Figure 2. Bofh the resected stomach and fhe gastrk remnant showed multlpie superficial ukeratkns containing lncluskn bodles in the gas&k mucosal glands character/&k of CMV Infection. 7’he parasitized ceils were of the chief cell variety and occurred both in situ and exfoliated into the tubular lumen.
tients with mucosai ulceration of the gastrointestinal tract. The association of impaired renal function in patients with cytomegaloviremia raises the question as to the possible role of the virus in precipitating allograft rejection. Support for this concept can be found in those patients with the clinical syndrome of CMV and impaired renal function who demonstrate classic histologic evidence of allograft rejection reversed by treatment with corticosteroids [3]. The previous histologic identification or recovery of the virus from the renal parenchyma [2,16,17,19] provides additional information that impaired renal function during episodes of viremia may be the result of either direct renal injury or graft rejection precipitated by the virus. The frequency of viruria, far moie common than microscopic identification of the virus in the kidney, suggests that impaired renal function may not be the result of the infection. The minimal amount of mononuclear cell infiltration, the moderate degree of renal enlargemelit, and the persistent urine volume of 500 to 1,000 ml/24 hours noted in the renal allograft in this patient mitigate against the usual clinical pattern of acute rejection. Although pyelonephritis may have contributed to the impaired renal function, it alone would not produce such a clinical syndrome. Altered renal function preceded by several days of fever and leukopenia, a common finding in those patients with nonfatal CMV infection, was clearly evident in our patient. Thus, an explanation for the decreasing renal
373
Diethelm
et al
function is not available solely on the basis of allograft rejection and suggests a direct involvement of the virus with the kidney parenchyma. Hepatic involvement secondary to CMV associated with an elevation of both serum glutamic oxalacetic transaminase and bilirubin levels and a decrease in serum albumin level has been recorded with varying frequency [2,9,10]. Microscopic examination of the liver in these circumstances has been reported to show normal architecture with areas of focal necrosis and mononuclear cell infiltration [2,10]. The profound decrease in serum albumin level noted in this patient and others in our experience has a serious prognosis even though the histologic appearance of the liver failed to demonstrate significant pathology. The comments by Rifkind [4] in 1965 seem most appropriate regarding CMV in renal allograft recipients and to this patient in particular. He noted that adequate explanations are not at hand for certain episodes of fever, pneumonia, gastrointestinal bleeding and hemorrhagic diatheses, hepatosplenomegaly, renal function impairment, and mental alterations, which have occurred after renal transplantation. His suggestion that some of these may be related to CMV infection has been supported by the present case in which many of these events were present including massive and fatal gastric hemorrhage with CMV present in the mucosa of both the resected stomach and the gastric remnant. Summary Generalized cytomegalovirus infection was associated with massive and ultimately fatal upper gastrointestinal bleeding in a renal allograft recipient and persisted even after subtotal gastric resection. The surgical specimen and the remaining stomach at autonsv revealed multinle suuerficial ulcerations with cytomegalic inclusion bodies within the gastric mucosa. Renal failure in the terminal stages of the patient’s illness required hemodialysis but did not seem to be the sole result of allograft rejection, suggesting that the renal dysfunction may be caused by the systemic viral infection. L
I
r
--A~
~~
References 1. Fine RN, Grushkin CM, Malekzadeh M, Wright HT: Cytomegalovirus syndrome following renal transplantation. Arch Surg 105: 564, 1972. 2. Millard PR. Herbertson BM, Nagington J, Evans DB: The morphological consequences and the significance of cytomegalovirus infection in renal transplant patients. Q J Med 42: 585, 1973.
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