Sirolimus and lymphocele formation after kidney transplantation: an immunosuppressive medication as co-factor for a surgical problem?

Markus Giessing1 and Klemens Budde2

1 Department of Urology 2 Department of Nephrology University Hospital Charité Humboldt University Berlin Berlin Germany E-mail: markus.giessing{at}charite.de

Sir,

Sirolimus has proven to be a powerful immunosuppressive agent for renal transplant recipients [1,2]. Side effects of sirolimus treatment include a higher frequency of lymphoceles [2], which can alter graft function due to ureteral compression. Infection of a lymphocele may cause more severe complications, such as vascular problems, infection and sepsis. The reasons for developing a lymphocele after renal transplantation are not yet clear, although lymphatic fluid from the recipient as well as from the donor organ seems to be involved [3,4].

In a retrospective study carried out between January 2000 and July 2001 we evaluated 85 consecutive renal transplant recipients for the development of lymphoceles. During this period, 13 out of these 85 patients received sirolimus, cyclosporin and methylprednisolone as immunosuppressive regimen. Following an initial loading-dose of 6 mg, sirolimus was given at 2 mg/day, aiming at trough levels between 5 and 15 ng/ml. The remaining 72 patients served as controls and received methylprednisolone, mycophenolate-mofetil, cyclosporin (low-risk patients, n=35) or tacrolimus (high-risk patients, n=37) and interleukin-2-receptor antibodies in some selected cases (n=23). Results were analysed by Student's t-test and chi-square test for proportions.

Patients in the sirolimus group had a higher age (43.2±18.9 vs 54.0±11.9; P<0.05) and more HLA mismatches (2.96±1.67 vs 3.92±1.0; P<0.05). The number of acute rejection episodes (24/72=33% vs 4/13=31%) was not significantly different. Eight recipients out of 13 (61%) in the sirolimus group developed lymphoceles ranging in size from ~70 to ~800 ml. Only one patient in the control group had a small, non-symptomatic lymphocele (P<0.001). Interestingly, five out of seven patients with chronic hepatitis B or C developed a lymphocele in the sirolimus group. Clinical presentation included a rise in serum creatinine in six cases and oedema of the leg and abdominal discomfort in two patients. One patient presented with an infected lymphocele. While treatment was not necessary in the single patient of the control group, seven of the eight sirolimus-treated patients with a lymphocele had to receive treatment (laparoscopic fenestration, n=5; percutaneous drainage, n=1; open surgical treatment, n=1). This was mainly due to the enormous size of the lymphoceles. Despite surgical treatment and nephrectomy, the patient with the infected lymphocele died from septic complications.

The previously described risk of up to 12–15% for lymphocele formation under treatment with sirolimus [2] was exceeded greatly in our analysis (61%). Risk factors [35], such as number of rejection episodes and heparin administration, were equal for both groups. Furthermore, the surgical technique was identical in all transplantations, performed by four experienced transplant urologists.

Coagulation parameters such as INR/TPT, aPTT and antithrombin III were normal or did not correlate with the development of a lymphocele. Fibrinogen levels were elevated in four of the 13 patients in the sirolimus group. Two of these four patients had a chronic hepatitis; three of the patients with an increased fibrinogen level developed a lymphocele. Normal platelet-count was present in all patients with a lymphocele. Also, the sirolimus trough levels aimed at (5–15 ng/ml) were not exceeded during the initial 4 weeks following kidney transplantation.

In the study, 11 of the 85 patients had hepatitis. Five of these 11 patients developed a lymphocele and all of them were on sirolimus, whereas two patients with hepatitis treated with sirolimus were free of complications. Hepatitis itself is not known to increase the risk of lymphocele formation. Therefore, the increased number of lymphoceles in the hepatitis patients of the sirolimus group may be caused by the sirolimus medication.

Therefore, we conclude that:

  1. Sirolimus may act as an inductor of lymphocele formation in renal transplant recipients.
  2. Sirolimus seems to promote lymphocele formation in renal transplant recipients presenting with chronic hepatitis. Reasons for this are yet unknown and may be due to a yet unrevealed interaction between sirolimus and the lymphatics or connective tissue.
  3. Sirolimus-treated renal transplant recipients should be monitored closely in an ultrasound-guided follow-up for early lymphocele detection to prevent possible complications.

References

  1. Chiu MI, Katz H, Berlin V. RAPT1, a mammalian homolog of yeast TOR, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci USA1994; 91:12574–12578[Abstract/Free Full Text]
  2. Kahan BD. Efficacy of sirolimus compared with azathioprine for reduction of acute renallograft rejection: a randomised multicentre study. Lancet2000; 356:194–202[CrossRef][ISI][Medline]
  3. Glass LL, Cockett ATK. Lymphoceles and management in urologic patients. Urology1998; 51:135–140[CrossRef][ISI][Medline]
  4. Khauli RB, Stoff JS, Lovewell T et al. Post-transplant lymphoceles: a critical look into the risk factors, pathophysiology and management. J Urol1993; 150:22–26[ISI][Medline]
  5. Bischof G, Rockenschaub S, Berlakovich G et al. Management of lymphoceles after kidney transplantation. Transpl Int1998; 11:277–280[CrossRef][ISI][Medline]




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