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Rapamycin rescue in adult liver recipients with post transplantation problems
644A
AASLD ABSTRACTS
HEPATOLOGY October 2001
1887
1888
DEVELOPMENT OF DE NOVO AUTOIMMUNE-LIKE HEPATITIS FOLLOWING LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS. Timothy Gunneson, Russell Wiesner, David Brandhagen, Transplant Ctr, Mayo Clinic, Rochester, MN; Lawrence Burgart, Dept of Pathology, Mayo Clinic, Rochester, MN; K V Narayanan Menon, Transplant Ctr, Mayo Clinic, Rochester, MN
IMPORTANCE OF THE TIMELY USE OF SIROLIMUS (SRL) PHARMACOKINETICS (PKT) TO FURTHER DECREASE THE INCIDENCE OF ACUTE CELLULAR REJECTION (ACR) IN LIVER TRANSPLANT RECIPIENTS (OLT). Carlos G Fasola, Laura L Christensen, Carol M Buxton, E d m u n d Q Sanchez, Ernesto P Molmenti, Thomas A Gonwa, Robert M Goldstein, Marlon F Levy, Goran B Klintmalm, Baylor Univ Medical Ctr, Dallas, TX
Background: Development of de novo autoimmune hepatitis / overlap syndromes following liver transplantation for primary biliary cirrhosis has recently been described. This phenomenon has not been described in patients transplanted for primary selerosing cholangitis (PSC). Aim: We report the development of de novo autoimmune-like hepatitis in 2 patients transplanted for PSC. Patients: A 61-yearold male underwent orthotopic liver transplantation (OLT) in November 1994 for well-defined PSC. Antinuclear antibody (ANA) was negative and gamma globulin (GG) levels were normal Standard triple immunosuppression with cyclosporine, prednisone and azathioprine was used. Prednisone was tapered and stopped in 1998 and azathioprine was discontinued in October 1999. In December 1999 liver enzyme elevations to twice the upper limit of normal were noted. Serum ANA subsequently turned strongly positive (> 12 U; normal < 1 U) and GG levels were elevated at 3.5 g/dL (normal 0.7 - 1.7 g/dL). Markers for other etiologies of acute hepatitis were negative. Liver biopsy revealed lymphoplasmacytic portal hepatitis, ductopenia and cirrhosis suggestive of an immune mediated hepatitis with recurrent PSC. There was no evidence of acute or chronic rejection. A cholangiogram showed minimal irregularity of the intrahepatic bile ducts. Prednisone and azathioprine were reinstituted with complete normalization of liver enzymes. HLA B8 haplotype was identified in this patient. A 52-year-old female who underwent OLT in August 1986 for PSC was also given standard triple immunosuppression with cyclosporine, azathioprine and prednisone. Azathioprine was discontinued in November 1991 with subsequent immunosuppression consisting of prednisone (2 mg daily) and low-dose cyclosporinc. In August 1999, an elevation in liver enzymes to 10 times the upper limit of normal was noted with a serum bilirubin of 4.3 mg/dL (normal 0.1 to 1.1). Serum ANA, smooth muscle antibody, and anti-liver kidney microsomal antibody were negative. GG levels were also normal. Liver biopsy demonstrated periportal and panacinar Iymphoplasmacytic infiltrates and bridging necrosis suggestive of an immune mediated hepatitis with no evidence of acute or chronic rejection. Prednisone 40 mg daily and azathioprine 50 mg daily were instituted with subsequent normalization of aminotransferases and serum bilirubin. A magnetic resonance cholangiogram was negative for recurrent PSC. With subsequent prednisone tapering and azathioprine discontinuation due to cytopenia, worsening liver enzymes and bflirubin was noted. Repeat liver biopsy revealed cirrhosis and lymphoplasmacytic infiltrates suggestive of autoimmune hepatitis. Prednisone was reinstituted with near normalization of liver enzyme abnormalities. HLA typing revealed the presence of B8 and DR3 haplotypes. Conclusion: This is the first report of de novo, steroid responsive, autoimmune-like hepatitis developing among patients transplanted for PSC in the context of prednisone tapering/withdrawal. Reduction ofimmunosuppression in patients transplanted for PSC must be done with caution and under careful supervision.
Methods: OLT 1998-1999 under SRL were analyzed. Group I (n=21): Cyclosporine (CSA) + Prednisolone (P) + SRL (15 mg x l ; then 5 rag/day); Group 1I (n=99): CSA + P, no SRL. PKT done for CSA and SRL. CSA levels daily for dose adjustments (DA) to a target level (SRL weekly): To assess ACR, a CSA/ SRL level ratio (R) was established. Demographics, UNOS status, ICU and hospital stay, infection rates, laboratory tests and survivals were all analyzed. Chi-Square and Fisher's exact tests were used for tables and Kaplan-Meier for actuarial survivals. Results: Most ACR occurred at 3 months post-OLT: 7/20 (35%) vs. 46/85 (54%) for ACR= 1 (p =0.38). Graft survival at 2 years: 77% vs. 90% (p = 0.15). The table shows level of CSA, SRL and CSA/SRL ratios in Group I with/without ACR (Group II=N.S.) Other parameters were not relevant. Conclusion: When CSA level was therapeutic, a CSA/SRL R<25 was found in no-ACR patients. ACR incidence could be even lower with proper SRL DA as done with other immunosuppression (IS.) SRL is an important addition to the OLT IS armamentarium to reduce the still elevated incidence of ACR,
SERUM CONCENTRATIONSOF CSA AND S,RLPOST.OLT (nglml) 1st Week 2nd Week 2nd Month ACR (n=7) Cyclosporine Sirolimus CSNSRL
3rd Month
266 _+46 11,2 ± 4~ 26.7 ± 13.22
247 + 85 10.6 + 5.03 33.6 + 15.84
271 + 56 t0.9 ± 4.5 31.7 + 8.4s
237 _+48 12.3 +_3.9 22,3 + 9.2
258 + 57 16.5 ± 62 ~ 17.2l_+6,22
313 + 74 15.4 ± 3.23 24,3+6.24
295 ± 82 14,7 ± 4.5 21.7+8,75
248 ± 66 16.4+_ 6.2 20.0+8.4
No-ACR (n=11) Cyclosporine Sirolimus CSA/SRL
1889
1890
RAPAMYCIN RESCUE IN ADULT LIVER RECIPENTS W I T H POST TRANSPLANTATION PROBLEMS. Regine Nessel, Marco Sass, Woifgang D Schareck, Rainer Wacke, Universit~t Rostock, Germany, Rostock Germany
SIGNIFICANCE OF POSITIVE CYTOTOXIC CROSSMATH IN ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION USING SMALL VOLUME OF GRAFT. Kyung-Suk Suh, Sang Beom Kim, Hyuk Joon Lee, Seong Hoon Kim, Kuhn Uk Lee, Seoul National University Hospital, Seoul Korea
Background. The therapeutic use of Rapamycin (RAP) has been shown as an option in selected cases of Tacrolimns (TAC) toxicity or failure. The conventional calcineurin inhibition provides effective immunosuppression but at the cost of nephrotoxicity, hypertonus and diabetes mellitns. Methods. Between 2/2000 and 3/2001 we treated a total of 20 liver and pancreas/kidney transplant recipients with RAP who received maintenance TAC. We report on 10 liver recipients (7 m a l e / 3 female) aged 26 to 63 years (mean 52 years) who developed under our conventional immunosuppression with TAC, Mycophenolate Mofetil and Corticosteroids either diabetes mellitus (n=3), tumor (n= 2), central nerve irritation (n = 1), chronic rejection ( n = 2), severe infection (n = 1) or nephrotoxicity (n = 1). Oral RAP was given once a day, 4 hours after the morning dose of TAC with a loading dose of 6rag followed by 2 mg daily. TAC was given twice daily in reduced dose. Results. RAP allowed a TAC dose reduction in all treated patients. No patient underwent a rejection episode during the observed time. RAP improved the blood sugar level of the patients with diabetes mellitus. We were also able to treat the patients with nephrotoxicity (n = 1) and central nerve irritation (n= 1) successful. Two patients died, one due to a severe pulmonary infection and the other because of a hepatocellular carcinoma. W e did not notice severe side effects. The observed mild increase of serum lipids two month after RAP administration was manageable. Conclusions. RAP is an effective rescue agent. Permitting dose reduction of TAC it can achieve measurable benefits in rejection, renal function and diabetes mellitus. Additional studies with the RAP+TAC combination are warranted to prevent calcineurin inhibitor related unwanted effects.
Background/aim Adult-to-adult living donor liver transplantation (LDLT) is limited by the critical mass of liver adequate to sustain life. Although small graft such as 0.59% graft-to-recipiem weight ratio (GRWR) and 25% of standard liver weight were successfully transplanted, the result of LDLT using small-for-size graft (SFG) is poor. The role of crossmatch in liver transplantation is controversial but positive crossmatch may play important role in adult to adult living donor liver transplantation (LDLT) using small-for-size graft (SFG). The aim of this study is to examine the significance of cytotoxic crossmatch in LDLT using SFG. Material/Methods Twenty-three cases of adult-toadult LDLT were performed at Seoul National University Hospital from January 1999 to June 2000. The subjects consist of 10 male and 13 female aged 42 on average. There were 10 cases of status 2A, 8 cases of status 2B and 5 cases of status 3 of UNOS status. The 23 recipients included hepatitis B related cirrhosis (20 cases), Wilsons disease, biliary atresia and autoimmune hepatitis. HLA crossmatch by lymphocytotoxicity and flow cytometry was routinely performed preoperatively. Factors which may influence survival such as UNOS status, age, sex, ABO compatibility, cytototoxic crossmatch, donor age, doner recipient relationships and graft recipient weight ratio (GRWR) were analyzed. Tacrolimns and steriods were used as immunosuppression. Lamivudine and hepatitis B immunoglobulin were used to prevent hepatitis B recurrence. Significance of difference was determined by Fisher's exact test. Results The weight of liver graft was 496.7-123.85gm. GRWR was 0.81+--0.16%. There were 7 cases (30%) of hospital mortality. There was one mortality (7.7%) in 13 male patients and 6 (60%) in 10 female patients. ABO was identical in 18 and compatible in 5 patients. These 2 patients who also had positive crossmatch died. But Sex and ABO compatibility were not significant factors (p=0.104). Crossmatch was positive in 4 patients who are all middle aged multiparous women. All four patients with positive crossmatch died. It was only a significant factor (p=0.001). Other factors did not show any significance. Conclusion Positive crossmatch is contraindication in LDLT using small for sized graft.
AASLD ABSTRACTS
HEPATOLOGY October 2001
1887
1888
DEVELOPMENT OF DE NOVO AUTOIMMUNE-LIKE HEPATITIS FOLLOWING LIVER TRANSPLANTATION FOR PRIMARY SCLEROSING CHOLANGITIS. Timothy Gunneson, Russell Wiesner, David Brandhagen, Transplant Ctr, Mayo Clinic, Rochester, MN; Lawrence Burgart, Dept of Pathology, Mayo Clinic, Rochester, MN; K V Narayanan Menon, Transplant Ctr, Mayo Clinic, Rochester, MN
IMPORTANCE OF THE TIMELY USE OF SIROLIMUS (SRL) PHARMACOKINETICS (PKT) TO FURTHER DECREASE THE INCIDENCE OF ACUTE CELLULAR REJECTION (ACR) IN LIVER TRANSPLANT RECIPIENTS (OLT). Carlos G Fasola, Laura L Christensen, Carol M Buxton, E d m u n d Q Sanchez, Ernesto P Molmenti, Thomas A Gonwa, Robert M Goldstein, Marlon F Levy, Goran B Klintmalm, Baylor Univ Medical Ctr, Dallas, TX
Background: Development of de novo autoimmune hepatitis / overlap syndromes following liver transplantation for primary biliary cirrhosis has recently been described. This phenomenon has not been described in patients transplanted for primary selerosing cholangitis (PSC). Aim: We report the development of de novo autoimmune-like hepatitis in 2 patients transplanted for PSC. Patients: A 61-yearold male underwent orthotopic liver transplantation (OLT) in November 1994 for well-defined PSC. Antinuclear antibody (ANA) was negative and gamma globulin (GG) levels were normal Standard triple immunosuppression with cyclosporine, prednisone and azathioprine was used. Prednisone was tapered and stopped in 1998 and azathioprine was discontinued in October 1999. In December 1999 liver enzyme elevations to twice the upper limit of normal were noted. Serum ANA subsequently turned strongly positive (> 12 U; normal < 1 U) and GG levels were elevated at 3.5 g/dL (normal 0.7 - 1.7 g/dL). Markers for other etiologies of acute hepatitis were negative. Liver biopsy revealed lymphoplasmacytic portal hepatitis, ductopenia and cirrhosis suggestive of an immune mediated hepatitis with recurrent PSC. There was no evidence of acute or chronic rejection. A cholangiogram showed minimal irregularity of the intrahepatic bile ducts. Prednisone and azathioprine were reinstituted with complete normalization of liver enzymes. HLA B8 haplotype was identified in this patient. A 52-year-old female who underwent OLT in August 1986 for PSC was also given standard triple immunosuppression with cyclosporine, azathioprine and prednisone. Azathioprine was discontinued in November 1991 with subsequent immunosuppression consisting of prednisone (2 mg daily) and low-dose cyclosporinc. In August 1999, an elevation in liver enzymes to 10 times the upper limit of normal was noted with a serum bilirubin of 4.3 mg/dL (normal 0.1 to 1.1). Serum ANA, smooth muscle antibody, and anti-liver kidney microsomal antibody were negative. GG levels were also normal. Liver biopsy demonstrated periportal and panacinar Iymphoplasmacytic infiltrates and bridging necrosis suggestive of an immune mediated hepatitis with no evidence of acute or chronic rejection. Prednisone 40 mg daily and azathioprine 50 mg daily were instituted with subsequent normalization of aminotransferases and serum bilirubin. A magnetic resonance cholangiogram was negative for recurrent PSC. With subsequent prednisone tapering and azathioprine discontinuation due to cytopenia, worsening liver enzymes and bflirubin was noted. Repeat liver biopsy revealed cirrhosis and lymphoplasmacytic infiltrates suggestive of autoimmune hepatitis. Prednisone was reinstituted with near normalization of liver enzyme abnormalities. HLA typing revealed the presence of B8 and DR3 haplotypes. Conclusion: This is the first report of de novo, steroid responsive, autoimmune-like hepatitis developing among patients transplanted for PSC in the context of prednisone tapering/withdrawal. Reduction ofimmunosuppression in patients transplanted for PSC must be done with caution and under careful supervision.
Methods: OLT 1998-1999 under SRL were analyzed. Group I (n=21): Cyclosporine (CSA) + Prednisolone (P) + SRL (15 mg x l ; then 5 rag/day); Group 1I (n=99): CSA + P, no SRL. PKT done for CSA and SRL. CSA levels daily for dose adjustments (DA) to a target level (SRL weekly): To assess ACR, a CSA/ SRL level ratio (R) was established. Demographics, UNOS status, ICU and hospital stay, infection rates, laboratory tests and survivals were all analyzed. Chi-Square and Fisher's exact tests were used for tables and Kaplan-Meier for actuarial survivals. Results: Most ACR occurred at 3 months post-OLT: 7/20 (35%) vs. 46/85 (54%) for ACR= 1 (p =0.38). Graft survival at 2 years: 77% vs. 90% (p = 0.15). The table shows level of CSA, SRL and CSA/SRL ratios in Group I with/without ACR (Group II=N.S.) Other parameters were not relevant. Conclusion: When CSA level was therapeutic, a CSA/SRL R<25 was found in no-ACR patients. ACR incidence could be even lower with proper SRL DA as done with other immunosuppression (IS.) SRL is an important addition to the OLT IS armamentarium to reduce the still elevated incidence of ACR,
SERUM CONCENTRATIONSOF CSA AND S,RLPOST.OLT (nglml) 1st Week 2nd Week 2nd Month ACR (n=7) Cyclosporine Sirolimus CSNSRL
3rd Month
266 _+46 11,2 ± 4~ 26.7 ± 13.22
247 + 85 10.6 + 5.03 33.6 + 15.84
271 + 56 t0.9 ± 4.5 31.7 + 8.4s
237 _+48 12.3 +_3.9 22,3 + 9.2
258 + 57 16.5 ± 62 ~ 17.2l_+6,22
313 + 74 15.4 ± 3.23 24,3+6.24
295 ± 82 14,7 ± 4.5 21.7+8,75
248 ± 66 16.4+_ 6.2 20.0+8.4
No-ACR (n=11) Cyclosporine Sirolimus CSA/SRL
1889
1890
RAPAMYCIN RESCUE IN ADULT LIVER RECIPENTS W I T H POST TRANSPLANTATION PROBLEMS. Regine Nessel, Marco Sass, Woifgang D Schareck, Rainer Wacke, Universit~t Rostock, Germany, Rostock Germany
SIGNIFICANCE OF POSITIVE CYTOTOXIC CROSSMATH IN ADULT TO ADULT LIVING DONOR LIVER TRANSPLANTATION USING SMALL VOLUME OF GRAFT. Kyung-Suk Suh, Sang Beom Kim, Hyuk Joon Lee, Seong Hoon Kim, Kuhn Uk Lee, Seoul National University Hospital, Seoul Korea
Background. The therapeutic use of Rapamycin (RAP) has been shown as an option in selected cases of Tacrolimns (TAC) toxicity or failure. The conventional calcineurin inhibition provides effective immunosuppression but at the cost of nephrotoxicity, hypertonus and diabetes mellitns. Methods. Between 2/2000 and 3/2001 we treated a total of 20 liver and pancreas/kidney transplant recipients with RAP who received maintenance TAC. We report on 10 liver recipients (7 m a l e / 3 female) aged 26 to 63 years (mean 52 years) who developed under our conventional immunosuppression with TAC, Mycophenolate Mofetil and Corticosteroids either diabetes mellitus (n=3), tumor (n= 2), central nerve irritation (n = 1), chronic rejection ( n = 2), severe infection (n = 1) or nephrotoxicity (n = 1). Oral RAP was given once a day, 4 hours after the morning dose of TAC with a loading dose of 6rag followed by 2 mg daily. TAC was given twice daily in reduced dose. Results. RAP allowed a TAC dose reduction in all treated patients. No patient underwent a rejection episode during the observed time. RAP improved the blood sugar level of the patients with diabetes mellitus. We were also able to treat the patients with nephrotoxicity (n = 1) and central nerve irritation (n= 1) successful. Two patients died, one due to a severe pulmonary infection and the other because of a hepatocellular carcinoma. W e did not notice severe side effects. The observed mild increase of serum lipids two month after RAP administration was manageable. Conclusions. RAP is an effective rescue agent. Permitting dose reduction of TAC it can achieve measurable benefits in rejection, renal function and diabetes mellitus. Additional studies with the RAP+TAC combination are warranted to prevent calcineurin inhibitor related unwanted effects.
Background/aim Adult-to-adult living donor liver transplantation (LDLT) is limited by the critical mass of liver adequate to sustain life. Although small graft such as 0.59% graft-to-recipiem weight ratio (GRWR) and 25% of standard liver weight were successfully transplanted, the result of LDLT using small-for-size graft (SFG) is poor. The role of crossmatch in liver transplantation is controversial but positive crossmatch may play important role in adult to adult living donor liver transplantation (LDLT) using small-for-size graft (SFG). The aim of this study is to examine the significance of cytotoxic crossmatch in LDLT using SFG. Material/Methods Twenty-three cases of adult-toadult LDLT were performed at Seoul National University Hospital from January 1999 to June 2000. The subjects consist of 10 male and 13 female aged 42 on average. There were 10 cases of status 2A, 8 cases of status 2B and 5 cases of status 3 of UNOS status. The 23 recipients included hepatitis B related cirrhosis (20 cases), Wilsons disease, biliary atresia and autoimmune hepatitis. HLA crossmatch by lymphocytotoxicity and flow cytometry was routinely performed preoperatively. Factors which may influence survival such as UNOS status, age, sex, ABO compatibility, cytototoxic crossmatch, donor age, doner recipient relationships and graft recipient weight ratio (GRWR) were analyzed. Tacrolimns and steriods were used as immunosuppression. Lamivudine and hepatitis B immunoglobulin were used to prevent hepatitis B recurrence. Significance of difference was determined by Fisher's exact test. Results The weight of liver graft was 496.7-123.85gm. GRWR was 0.81+--0.16%. There were 7 cases (30%) of hospital mortality. There was one mortality (7.7%) in 13 male patients and 6 (60%) in 10 female patients. ABO was identical in 18 and compatible in 5 patients. These 2 patients who also had positive crossmatch died. But Sex and ABO compatibility were not significant factors (p=0.104). Crossmatch was positive in 4 patients who are all middle aged multiparous women. All four patients with positive crossmatch died. It was only a significant factor (p=0.001). Other factors did not show any significance. Conclusion Positive crossmatch is contraindication in LDLT using small for sized graft.