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Chylous Ascites in a Renal Transplant Recipient Under Sirolimus (Rapamycin) Treatment
Chylous Ascites in a Renal Transplant Recipient Under Sirolimus (Rapamycin) Treatment G. Castro C. Freitas, I. Beirão, G. Rocha, A.C. Henriques, and A. Cabrita ABSTRACT Ascites is a rare complication of renal transplantation. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. While technical complications of the procedure are the most frequent cause, portal hypertension and graft rejection are other causes. Ascites can occur after renal transplantation independent of kidney function. Usually, a time relation can be made between the surgical procedure and ascites development. Chylous ascites is still more uncommon; it is usually related to traumatic lymphatic injury. Drugs are rarely associated with the genesis of ascites. Sirolimus has been associated with a high rate of lymphoceles, lymphedema, and pulmonary alveolar proteinosis. The exact mechanisms remain unknown. The risk for lymphocele formation with sirolimus is 12% to 15%. Ascites is an adverse effect with an incidence between 3% and 20%, but no relation between sirolimus and chylous ascites was previously established. We present a clinical report of chylous ascites in a renal transplant patient under sirolimus therapy; our investigation pointed to sirolimus as the cause.
A
SCITES OCCURS EITHER as a result of technical complications of the transplant procedure or from medical reasons that include portal hypertension and graft rejection.1,2 Ascites after kidney transplantation is rare, occurring with normal or abnormal kidney function. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. Technical complications of the procedure are the most frequent cause.3 Chylous ascites develops when disruption of the lymphatic system occurs, due to traumatic or obstructive causes. Its milky appearance is due to a high content of triglycerides, more than 200 mg/dL (although some authors use a cutoff value of 110 mg/dL).4 Obstruction of lymph flow due to abdominal malignancy or cirrhosis accounts for over two-thirds of all cases in Western countries. Infections like tuberculosis are responsible for the majority of cases in developing countries.5 Successful treatment depends on correction of the underlying cause. Chylous ascites is a rare occurrence after renal transplantation. In the literature we found only three cases,6 – 8 all of which occurred at a short interval of traumatic injury. Herein we have reported a case of chylous ascites in a renal transplant recipient under sirolimus therapy.
CASE REPORT A 38-year-old man with chronic renal failure due to Alport syndrome underwent cadaveric donor renal transplantation in 1999. The initial immunosuppressive therapy was cyclosporine, azathioprine, and prednisone. Five years after transplantation, he presented with an increased serum creatinine level related to high cyclosporine levels; cyclosporine was switched to sirolimus. In May 2005, he developed a perinephric fluid collection. A diagnosis of lymphocele was established, and surgical drainage performed. One year later, grade 1 clean ascites (small volume) was on abdominal ultrasound examination. A diagnostic paracentesis revealed a transudate. The patient was successfully treated with furosemide. Cytological examination and bacterial culture of the ascitic fluid were negative. Five months later, he underwent laparoscopic colecystectomy due to lithiasis; a grade 1 ascites was observed during surgery. The analysis was similar to the previous one. Two months later, he presented with increased abdominal size, without other symptoms or abnormal signs. Ultrasonography and paracentesis yielded
From the Department of Nephrology, Hospital Geral de Santo António, Porto, Portugal. Address reprint requests to Guiomar Castro, MD, Department of Nephrology, Hospital Geral de Santo António, Largo Professor Abel Salazar, 2, Porto, Portugal. E-mail: guiomarcastro@ hotmail.com
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.02.074
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1756
Transplantation Proceedings, 40, 1756 –1758 (2008)
CHYLOUS ASCITES IN A RENAL RECIPIENT
1757
Table 1. Laboratory Data of Ascitic Fluid and Serum
Triglyceride level (mg/dL) Cell count (cel/L) Total protein (g/dL) Albumin (g/dL) Glucose (mg/dL) Lactate dehydrogenase (U/L) Bacteriologic culture Adenosine deaminase (U/L) Cytology Amylase (U/L)
Ascitic fluid
Serum
189 185 lymphocytes 1.9 1.6 95 45 Negative 4 Negative for malignant cells 20
88 — 7.7 4.5 86 176 Negative — 31
drainage of 900 mL of milky, cloudy appearing fluid, suggestive of chylous ascites. Laboratory data are summarized in Table I. The serum ascites albumin gradient suggested portal hypertension, but he did not have signs of chronic liver disease on physical examination or laboratory or radiological study. Serum creatinine was 1.5 mg/dL and serum urea was 92 mg/dL. No proteinuria was detected. Doppler abdominal ultrasound did not show abnormalities. Upper endoscopy did not reveal esophageal varices or signs of portal hypertension. Cervical, thoracic, and abdominal computed tomographies excluded malignancies and obstructive causes of lymph vessels. No pleural effusion was identified. Cardiac ultrasound examination was normal. Ascitic fluid cytology showed lymphocytes without malignant cells. Bacterial cultures (ascitic fluid and blood) were negative, including to Mycobacterium tuberculosis. Excluding the main causes of chylous ascites, sirolimus toxicity was considered; sirolimus was switched to cyclosporine. The patient also used a low-fat diet and medium-chain triglyceride supplements and diuretic therapy. One month later, an abdominal ultrasound showed the ascites to be gone. A free diet regimen was then implemented; the patient remained free of symptoms at 3 months later.
DISCUSSION
Lymphoceles complicate 18% of renal transplants, usually occurring in the first 6 months posttransplantation.9 They can cause symptoms secondary to compression of blood vessels; edema of the leg or compression of the transplant ureter,10 but the majority remain asymptomatic. Fenestration of the lymphocele to the peritoneum is a cause of chylous ascites.7 In our patient, a lymphocele developed 6 years after transplantation, suggesting an underling mechanism other than surgical lymph vessel injury. He underwent surgical correction of the lymphocele. A transudative ascites developed 1 year later and a relation between the two events was established. After 5 months, ascites recurred and 2 months later became chylous. Causes other than a traumatic injury were investigated, including malignancy, infection, portal hypertension, and drug side effects. We detected a temporal relationship with the introduction of sirolimus. Sirolimus, a macrolide antibiotic with potent immunosuppressive effects, has increasing use in transplantation. It has been associated with a high rate of lymphoceles,10
lymphedema,11 and pulmonary alveolar proteinosis.12 The exact mechanisms remain unknown.11 The risk for lymphocele formation with sirolimus is 12% to 15%.13 Ascites is an adverse effect with an incidence between 3% and 20% (sirolimus: drug information, Lexi-Comp, Inc), but no relation between sirolimus and chylous ascites was previously established. We found only three cases of chylous ascites reported among renal transplant recipients: two cases that occurred within the first month posttransplant were related to surgical injury,6,7 and the third occurred 1 year after renal transplantation, related to a renal graft biopsy.14 Our patient was free of surgical interventions in the first 6 years posttransplantation. The lymphocele, which developed after this period, occurred after beginning sirolimus therapy and could have been related to that. No other surgical interventions were performed until the laparoscopic colecystectomy, which was performed 2 years later. During this surgery, a grade 1 clean ascites was already detected. The authors found only one description of chylous ascites development at 2 weeks after laparoscopic colecystectomy, which improved only after surgical correction.8 After the exclusion of the main causes of chylous ascites, the authors considered the introduction of sirolimus to be a potential cause of this complication. Despite diuretic and nutritional management, the remission of the ascites within a month after sirolimus withdrawal and the lack of recurrence suggest a relationship between the drug and ascites development. Nutritional management, a long-term treatment, usually is not sufficient to resolve ascites; recurrence is frequent with diet withdrawal. In this case, no recurrence occurred after diet withdrawal, suggesting correction of the underling cause. No recurrence suggested that chylous ascites was related to sirolimus therapy.
REFERENCES 1. Popli S, Chen W, Nakamoto S, et al: Haemodialysis ascites in anephric patients. Clin Nephrol 15:203, 1981 2. Horn S, Holzer H, Horina JH: Spontaneous bacterial peritonitis in a patient with nephrogenic ascites during an episode of acute renal transplant rejection. Am J Kidney Dis 27:441, 1996 3. Franz M, Horl W: The patient with end-stage renal failure and ascites. Nephrol Dial Transplant 12:1070, 1997 4. Cárdenas A, Chopra S: Chylous ascites. Am J Gastroenterol 97:1986, 2002 5. Cardenas A, Gelrud A, Chopra S: Chylous, bloody, and pancreatic ascites. Available from: http://www.uptodate.com. Accessed March 2008 6. Itoh k, Tanda K, Kato C, et al: Intraperitoneal leakage of tecnesium-99-m-DTPA following renal transplantation: a sign of chylous ascites. J Nucl Med 35:93, 1994 7. Liu WC, Kuo MC, Wu WJ, et al: Chylous ascites after renal transplantation—a case report. Nephrol Dial Transplant 21:3336, 2006 8. Jensen EH, Weiss CA: Management of chylous ascites after laparoscopic cholecystectomy using minimally techniques: a case report and literature review. Am Surg 72:60, 2006
1758 9. Duepree HJ, Fornara P, Lewejohann JC, et al: Laparoscopic treatment of lymphoceles in patients after renal transplantation. Clin Transplant 15:375, 2001 10. Giessing M, Fischer TJ, Deger S, et al: Increased frequency of lymphoceles under treatment with sirolimus following renal transplantation: a single center experience. Transplant Proc 34: 1815, 2002 11. Al-Otaibi T, Ahamed N, Nampoory MRN, et al: Lymphedema: an unusual complication of sirolimus therapy. Transplant Proc 39:1207, 2007
CASTRO, FREITAS, BEIRÃO ET AL 12. Pedroso SL, Martins LS, Sousa S, et al: Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus. Transpl Int 20:291, 2007 13. Kahan BD: Efficacy of sirolimus compared with azathioprine for reduction of acute renallograft rejection: a randomised multicenter study. Lancet 356:194, 2000 14. Kulkarni S, Burns A, Al-Akraa M: Severe ascites following renal transplant biopsy caused by a rupture of a subcapsular lymphocele: treated successfully by retroperitonealization. Nephrol Dial Transplant 19:1022, 2004
A
SCITES OCCURS EITHER as a result of technical complications of the transplant procedure or from medical reasons that include portal hypertension and graft rejection.1,2 Ascites after kidney transplantation is rare, occurring with normal or abnormal kidney function. Ascites has been reported after kidney transplantation due to rejection, decapsulation of the graft, urinary or vascular leak, lymphocele, transudation, or infection. Technical complications of the procedure are the most frequent cause.3 Chylous ascites develops when disruption of the lymphatic system occurs, due to traumatic or obstructive causes. Its milky appearance is due to a high content of triglycerides, more than 200 mg/dL (although some authors use a cutoff value of 110 mg/dL).4 Obstruction of lymph flow due to abdominal malignancy or cirrhosis accounts for over two-thirds of all cases in Western countries. Infections like tuberculosis are responsible for the majority of cases in developing countries.5 Successful treatment depends on correction of the underlying cause. Chylous ascites is a rare occurrence after renal transplantation. In the literature we found only three cases,6 – 8 all of which occurred at a short interval of traumatic injury. Herein we have reported a case of chylous ascites in a renal transplant recipient under sirolimus therapy.
CASE REPORT A 38-year-old man with chronic renal failure due to Alport syndrome underwent cadaveric donor renal transplantation in 1999. The initial immunosuppressive therapy was cyclosporine, azathioprine, and prednisone. Five years after transplantation, he presented with an increased serum creatinine level related to high cyclosporine levels; cyclosporine was switched to sirolimus. In May 2005, he developed a perinephric fluid collection. A diagnosis of lymphocele was established, and surgical drainage performed. One year later, grade 1 clean ascites (small volume) was on abdominal ultrasound examination. A diagnostic paracentesis revealed a transudate. The patient was successfully treated with furosemide. Cytological examination and bacterial culture of the ascitic fluid were negative. Five months later, he underwent laparoscopic colecystectomy due to lithiasis; a grade 1 ascites was observed during surgery. The analysis was similar to the previous one. Two months later, he presented with increased abdominal size, without other symptoms or abnormal signs. Ultrasonography and paracentesis yielded
From the Department of Nephrology, Hospital Geral de Santo António, Porto, Portugal. Address reprint requests to Guiomar Castro, MD, Department of Nephrology, Hospital Geral de Santo António, Largo Professor Abel Salazar, 2, Porto, Portugal. E-mail: guiomarcastro@ hotmail.com
0041-1345/08/$–see front matter doi:10.1016/j.transproceed.2008.02.074
© 2008 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1756
Transplantation Proceedings, 40, 1756 –1758 (2008)
CHYLOUS ASCITES IN A RENAL RECIPIENT
1757
Table 1. Laboratory Data of Ascitic Fluid and Serum
Triglyceride level (mg/dL) Cell count (cel/L) Total protein (g/dL) Albumin (g/dL) Glucose (mg/dL) Lactate dehydrogenase (U/L) Bacteriologic culture Adenosine deaminase (U/L) Cytology Amylase (U/L)
Ascitic fluid
Serum
189 185 lymphocytes 1.9 1.6 95 45 Negative 4 Negative for malignant cells 20
88 — 7.7 4.5 86 176 Negative — 31
drainage of 900 mL of milky, cloudy appearing fluid, suggestive of chylous ascites. Laboratory data are summarized in Table I. The serum ascites albumin gradient suggested portal hypertension, but he did not have signs of chronic liver disease on physical examination or laboratory or radiological study. Serum creatinine was 1.5 mg/dL and serum urea was 92 mg/dL. No proteinuria was detected. Doppler abdominal ultrasound did not show abnormalities. Upper endoscopy did not reveal esophageal varices or signs of portal hypertension. Cervical, thoracic, and abdominal computed tomographies excluded malignancies and obstructive causes of lymph vessels. No pleural effusion was identified. Cardiac ultrasound examination was normal. Ascitic fluid cytology showed lymphocytes without malignant cells. Bacterial cultures (ascitic fluid and blood) were negative, including to Mycobacterium tuberculosis. Excluding the main causes of chylous ascites, sirolimus toxicity was considered; sirolimus was switched to cyclosporine. The patient also used a low-fat diet and medium-chain triglyceride supplements and diuretic therapy. One month later, an abdominal ultrasound showed the ascites to be gone. A free diet regimen was then implemented; the patient remained free of symptoms at 3 months later.
DISCUSSION
Lymphoceles complicate 18% of renal transplants, usually occurring in the first 6 months posttransplantation.9 They can cause symptoms secondary to compression of blood vessels; edema of the leg or compression of the transplant ureter,10 but the majority remain asymptomatic. Fenestration of the lymphocele to the peritoneum is a cause of chylous ascites.7 In our patient, a lymphocele developed 6 years after transplantation, suggesting an underling mechanism other than surgical lymph vessel injury. He underwent surgical correction of the lymphocele. A transudative ascites developed 1 year later and a relation between the two events was established. After 5 months, ascites recurred and 2 months later became chylous. Causes other than a traumatic injury were investigated, including malignancy, infection, portal hypertension, and drug side effects. We detected a temporal relationship with the introduction of sirolimus. Sirolimus, a macrolide antibiotic with potent immunosuppressive effects, has increasing use in transplantation. It has been associated with a high rate of lymphoceles,10
lymphedema,11 and pulmonary alveolar proteinosis.12 The exact mechanisms remain unknown.11 The risk for lymphocele formation with sirolimus is 12% to 15%.13 Ascites is an adverse effect with an incidence between 3% and 20% (sirolimus: drug information, Lexi-Comp, Inc), but no relation between sirolimus and chylous ascites was previously established. We found only three cases of chylous ascites reported among renal transplant recipients: two cases that occurred within the first month posttransplant were related to surgical injury,6,7 and the third occurred 1 year after renal transplantation, related to a renal graft biopsy.14 Our patient was free of surgical interventions in the first 6 years posttransplantation. The lymphocele, which developed after this period, occurred after beginning sirolimus therapy and could have been related to that. No other surgical interventions were performed until the laparoscopic colecystectomy, which was performed 2 years later. During this surgery, a grade 1 clean ascites was already detected. The authors found only one description of chylous ascites development at 2 weeks after laparoscopic colecystectomy, which improved only after surgical correction.8 After the exclusion of the main causes of chylous ascites, the authors considered the introduction of sirolimus to be a potential cause of this complication. Despite diuretic and nutritional management, the remission of the ascites within a month after sirolimus withdrawal and the lack of recurrence suggest a relationship between the drug and ascites development. Nutritional management, a long-term treatment, usually is not sufficient to resolve ascites; recurrence is frequent with diet withdrawal. In this case, no recurrence occurred after diet withdrawal, suggesting correction of the underling cause. No recurrence suggested that chylous ascites was related to sirolimus therapy.
REFERENCES 1. Popli S, Chen W, Nakamoto S, et al: Haemodialysis ascites in anephric patients. Clin Nephrol 15:203, 1981 2. Horn S, Holzer H, Horina JH: Spontaneous bacterial peritonitis in a patient with nephrogenic ascites during an episode of acute renal transplant rejection. Am J Kidney Dis 27:441, 1996 3. Franz M, Horl W: The patient with end-stage renal failure and ascites. Nephrol Dial Transplant 12:1070, 1997 4. Cárdenas A, Chopra S: Chylous ascites. Am J Gastroenterol 97:1986, 2002 5. Cardenas A, Gelrud A, Chopra S: Chylous, bloody, and pancreatic ascites. Available from: http://www.uptodate.com. Accessed March 2008 6. Itoh k, Tanda K, Kato C, et al: Intraperitoneal leakage of tecnesium-99-m-DTPA following renal transplantation: a sign of chylous ascites. J Nucl Med 35:93, 1994 7. Liu WC, Kuo MC, Wu WJ, et al: Chylous ascites after renal transplantation—a case report. Nephrol Dial Transplant 21:3336, 2006 8. Jensen EH, Weiss CA: Management of chylous ascites after laparoscopic cholecystectomy using minimally techniques: a case report and literature review. Am Surg 72:60, 2006
1758 9. Duepree HJ, Fornara P, Lewejohann JC, et al: Laparoscopic treatment of lymphoceles in patients after renal transplantation. Clin Transplant 15:375, 2001 10. Giessing M, Fischer TJ, Deger S, et al: Increased frequency of lymphoceles under treatment with sirolimus following renal transplantation: a single center experience. Transplant Proc 34: 1815, 2002 11. Al-Otaibi T, Ahamed N, Nampoory MRN, et al: Lymphedema: an unusual complication of sirolimus therapy. Transplant Proc 39:1207, 2007
CASTRO, FREITAS, BEIRÃO ET AL 12. Pedroso SL, Martins LS, Sousa S, et al: Pulmonary alveolar proteinosis: a rare pulmonary toxicity of sirolimus. Transpl Int 20:291, 2007 13. Kahan BD: Efficacy of sirolimus compared with azathioprine for reduction of acute renallograft rejection: a randomised multicenter study. Lancet 356:194, 2000 14. Kulkarni S, Burns A, Al-Akraa M: Severe ascites following renal transplant biopsy caused by a rupture of a subcapsular lymphocele: treated successfully by retroperitonealization. Nephrol Dial Transplant 19:1022, 2004