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Hepatotoxicity Associated With Cyclosporine Monitoring Using C2 Recommendations in Adults Renal Recipients Receiving Ketoconazole
Hepatotoxicity Associated With Cyclosporine Monitoring Using C2 Recommendations in Adults Renal Recipients Receiving Ketoconazole C. Videla, J. Vega, and H. Borja Abstract Following the change, in the way we monitored cyclosporine (CsA) levels in January 2000 namely from C0 to C2 concentrations, in renal “de novo” allograft recipients, some patients treated with concomitant ketoconazole experienced liver toxicity, a complication that had not been previously seen with CsA monitoring using C0. Therefore, we decided to compare the outcomes of patients transplanted using CsA levels monitored by C0 (1998 to 1999) who also had simultaneous C2 determinations (group A) with those of recipients transplanted after 2000 (group B). All received steroids, azathioprine, and CsA plus ketoconazole. Recipients were followed for at least a year after transplantation. Patients in group B showed higher CsA C2 levels, AUC concentrations, and drug doses during the immediate postsurgical period, and at 2 weeks as well as 4 and 6 months posttransplantation. Six group B patients (26%) but no group A recipients displayed, severe liver toxicity characterized by jaundice, elevated liver enzymes, with negative serological tests for CMV, HVC, and HVB. There was a correlation between the GOT and the C2 CsA levels; both normalized 15 to 55 days after CsA dose reduction. High C2 CsA levels, which have been recommended when the drug is used alone in renal transplantation, cannot be used in patients taking ketoconazole, because C2 neither represents nor correlates with AUC drug exposure. Thus high C2 levels may produce liver toxicity.
M
OST REPORTS of cyclosporine (CsA)-related liver dysfunction were published during the early era, when higher doses were used. Pharmacokinetic data showed that patients with hepatotoxicity had increased CsA bioavailability and/or decreased clearance, resulting in elevated trough levels.1 We have reported that concomitant use of ketoconazole with CsA prolongs CsA half-life leading to higher drug concentration curves versus time (AUC) in adult recipients of a renal allograft. Furthermore the peak concentrations are higher than those seen with CsA combined with diltiazem or CsA alone.2 No patient showed evidence of hepatotoxicity using Sandimmun or Neoral (Novartis) either alone or in combination when closely was performed by monitoring C0.3,4 Following the publication of C2 monitoring guidelines to achieve better CsA exposure5 we adopted them for patients cotreated with ketoconazole. Several kidney allograft recipients monitored with C2 levels displayed abnormal liver function tests during the immediate posttransplant period. Several mechanisms have been proposed to explain CsA hepatotoxicity, including changes in intracellular hepatizcontent of glutathione re-
lated to detoxification reactions and altered redox balance of the cell.6,7 In addition enhanced cholestasis may be caused by decreased biliary flow affecting bile acid transport 1,7 or increased susceptibility due to chronic hepatitis virus in the major canaliculae C.8 One author has presented an explicit diagram showing the mechanisms of liver injury.9 Here in we present the cases of six adult renal allograft recipients who received CsA plus ketoconazole therapy using C2 monitory and experiencing unusual life-threatening liver toxicity. PATIENTS AND METHODS All renal allograft recipients, transplanted between January 1998 and December 2002 were treated with steroids, azathioprine, CsA-ME, and ketoconazole. Their CsA levels were monitored by C0 (most of the patients have simultaneously determining C2 levels From the Nephrology Department, G. Fricke Hospital, Viña del Mar, Chile. Address reprint requests to Dr C. Videla, 5 Norte 1035, Viña del Mar, Chile. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.09.011
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1574
Transplantation Proceedings, 37, 1574 –1576 (2005)
HEPATOXICITY AND CYCLOSPORINE MONITORING due to an AUC of 3 points; group A; n ⫽ 15) or by C2 values (group B, n ⫽ 23). We excluded patients with primary graft, nonfunction, pregnancy, children, and those who did not receive ketoconazole. Table 1 describes the demographics and outcomes during both monitoring periods. Immunosuppressive drugs administered included Neoral, prednisone, and azathioprine. Neoral was given as a single morning dose starting at 8 mg/kg immediately prior to transplantation and adjusted afterward to achieve either C0 ⫽ 350 to 550 ng/mL or C2 ⫽ 1200 to 1500 ng/mL during the first month posttransplant. Prednisone was tapered by 10 mg weekly until reaching 0.12 mg/kg. Azathioprine was administered at a dose of 2 mg/kg daily and ketoconazole (200 mg morning doses daily). CsA blood level determinations were performed using a nonspecific commercial radioimmunoassay kit immediately pretransplant and adjusted to achieve C0 ⫽ 350 to 550 ng/mL and C2 ⫽ 1200 to 1500 ng/mL during the first month. A three-point AUC was calculated using the 1-, 2-, and 6-hour blood levels (according a formula obtained by numeric integration). Patients had their liver enzymes evaluated prior to starting ketoconazole administration and at 3 weeks posttransplantation. Hepatobiliary echotomography, CMV antigenemia, RNA HCV detection by PCR, and HBV surface antigen were performed, whenever hepatic damage was suspected. CsA levels were monitored weekly during the first 3 months and then every other month until month 6. Statistical evaluation was performed using an unpaired onetailed Student t test with Pearson correlation.
RESULTS
There were 60 C2 levels performed among group A patients and 596 group B recipients. During the early 2-week, posttransplant period, all levels were significantly higher among group B than group A recipients: 1292 ⫾ 466 versus 573 ⫾ 249 ng/mL and 1148 ⫾ 328 versus 455 ⫾ 145 respectively. From the 6th week through the 4th and/or the 6th month this levels were 966 ⫾ 489 versus 409 ⫾ 118 ng/mL (P ⬍ .01). There was a highly significant increase in the CsA dose per kilogram comparing the 2000 to 2001 periods (9.9 ⫾ 1.87 mg/kg during the first posttransplant day) 1998 to 1999 (5.3 ⫾ 1.9 mg/kg) (P ⬍ .01). Furthermore at the 14th posttransplant day in the 2000 to 2002 period the dose was 11.5 ⫾ 1.66 mg/kg When ketoconazole was introduced there was also an increased CsA dose (over 30%) during the same time periods from 1.4 ⫾ 0.5 mg/kg to 1.83 ⫾ 0.29 (P ⬍ .01). The reason was a trend to raise CsA drug exposure to prevent acute rejections during the highest risk time immediately posttransplant period. Six patients in group B but none in group A showed altered liver function tests. All these subjects displayed elevated transaminase levels and three of them also had severe jaundice, with one patient achieving a serum bilirubin level of 12.87 mg/dL. Liver toxicity occurred between the 4th and 21st posttransplant days. The CsA dose was clearly related to the C2 value and the oxaloacetic transaminase serum levels (r2: 0.36, P ⬍ .05). Ketoconazole was discontinued when liver toxicity was suspected, after excluding other causes for liver enzyme changes, including cho-
1575 Table 1. Characteristics of Adult Renal Recipients Immunosuppressed With Cyclosporine Plus Ketoconazole in Different Time Periods 1998–1999
n Age (years) Donor (Cadaver) Sex (M/F) Time on dialysis (months) Cold ischemia time (hours) HLA Compatibility B DR MM B DR Serum creatinine (mg/dL) 3 months 1 year 2 year
2000–2002
15 42 ⫾ 10.7 15 8/7 42 ⫾ 11
23 36.7 ⫾ 13 21 12/11 52.64 ⫾ 31.3
21.5 ⫾ 5
20.2 ⫾ 4.4
1.9 ⫾ 0.8 0.9 ⫾ 0.6 1998
1999
2.34 ⫾ 0.85 1.1 ⫾ 0.4 2000–02
1.25 ⫾ 0.24 1.3 ⫾ 0.28 1.3 ⫾ 0.23
1.68 ⫾ 0.22 1.77 ⫾ 0.58 1.66 ⫾ 0.61
1.59 ⫾ 0.57 1.48 ⫾ 0.42 1.49 ⫾ 0.34
lestasis, biliary flow obstruction, or viral infection (CMV, HCV, HBV). When the CsA dose was reduced, the serum transaminase, gammaglutamyl transpeptidase, and bilirrubin levels normalized within 15 to 55 days. Following CsA dose reduction one patient required a switch from azathioprine to mycophenolate mophetil due to increased rejection risk. Ketoconazole was subsequently reincorporate namely at 12 to 120 days in all patients, except for one 65 years of age, who was kept only on steroids and low-dose CsA. Follow-up controls of these patients did not show any toxicity complications. Renal function remained stable in both groups during the first year of follow-up. Nevertheless, patients in group B, monitored using C2, showed a trend, albeit not statistically significant, toward poorer graft function than those in group A during the first year posttransplant. DISCUSSION
Early in the 1980s it had been suggested that CsA and ketoconazole could be used together only with extreme caution and with regular CsA blood level measurements.10 The CsA toxicity profiles in patients monitored using C2 blood levels have been reported to show less renal and neurological toxicity, while liver toxicity has been reported to be rare using either C0 or C2 to monitor CSA levels. AUC is the most accurate predictor of CsA immunosuppression. It correlates well with acute cellular rejection and graft loss at 1 year post–renal transplant. In our patients, AUC was higher among patients with hepatotoxicity. None experienced acute rejection episodes. We do not have any explanation for the liver toxicity without nephrotoxicity in our patients. In previous communications2– 4 we did not observe any evidence of altered liver function tests. However, when we used higher CsA doses coadministered with
1576
ketoconazole at AUC above 5500 to 6000 ng h/mL range, cholestasis disorder appeared associated with conjugated hiperbilirubinemia and moderate hepatic cytosolic enzyme elevations. Likewise, elevated CsA C2 levels recommended during the first month11,12 cannot be validated in patients taking ketoconazole, because C2 values over 1500 to 1700 ng/mL lead to liver toxicity, requiring CsA dose reduction (and in more severe cases, discontinuation of ketoconazole). It is clear that ketoconazole flattens the CsA AUC. Thus C2 levels are no longer representative of the AUC exposure. Thus, use of C2 to monitor patients treated with CsA plus ketoconazole will mean a risk of CsA overexposure and toxicity as seen in our patients. REFERENCES 1. Kowdley K, Keeffe E: Gastroenterology Clinics of North America 24:991, 1995
VIDELA, VEGA, AND BORJA 2. Foradori A, Mezzano S, Videla C, et al: Transplant Proc 30:1685, 1998 3. Videla C, Vega J, Borja H, et al: Rev Med Chile 125:438, 1997 4. Vega J, Videla C, Borja H, et al: Nefrologia Latinoamericana 7:2, 2000 5. Mahalati K, Belitsky P, West K, et al: J Am Soc Nephrol 12:823, 2001 6. Wolf A, Trendelemburg C, Diez Hernandez P, et al: Transplant Proc 26:2912, 1994 7. Galán A, Fernéndez E, Morán D, et al: Clin Exp Pharmacolo Physiol 22:260, 1995 8. Horina J, Wirnsberger G, Kenner L, et al: Transplantation 56:1091, 1993 9. Lee W: N Engl J Med 349:474, 2003 10. White D, Blatchford N, Cauwenbergh G: Transplantation 37:214, 1984 11. Levy G: Transplant Proc 31:1654, 1999 12. Mahan N, Cardella C, Cattran D, et al: Transplant Proc 33:3098, 2001
M
OST REPORTS of cyclosporine (CsA)-related liver dysfunction were published during the early era, when higher doses were used. Pharmacokinetic data showed that patients with hepatotoxicity had increased CsA bioavailability and/or decreased clearance, resulting in elevated trough levels.1 We have reported that concomitant use of ketoconazole with CsA prolongs CsA half-life leading to higher drug concentration curves versus time (AUC) in adult recipients of a renal allograft. Furthermore the peak concentrations are higher than those seen with CsA combined with diltiazem or CsA alone.2 No patient showed evidence of hepatotoxicity using Sandimmun or Neoral (Novartis) either alone or in combination when closely was performed by monitoring C0.3,4 Following the publication of C2 monitoring guidelines to achieve better CsA exposure5 we adopted them for patients cotreated with ketoconazole. Several kidney allograft recipients monitored with C2 levels displayed abnormal liver function tests during the immediate posttransplant period. Several mechanisms have been proposed to explain CsA hepatotoxicity, including changes in intracellular hepatizcontent of glutathione re-
lated to detoxification reactions and altered redox balance of the cell.6,7 In addition enhanced cholestasis may be caused by decreased biliary flow affecting bile acid transport 1,7 or increased susceptibility due to chronic hepatitis virus in the major canaliculae C.8 One author has presented an explicit diagram showing the mechanisms of liver injury.9 Here in we present the cases of six adult renal allograft recipients who received CsA plus ketoconazole therapy using C2 monitory and experiencing unusual life-threatening liver toxicity. PATIENTS AND METHODS All renal allograft recipients, transplanted between January 1998 and December 2002 were treated with steroids, azathioprine, CsA-ME, and ketoconazole. Their CsA levels were monitored by C0 (most of the patients have simultaneously determining C2 levels From the Nephrology Department, G. Fricke Hospital, Viña del Mar, Chile. Address reprint requests to Dr C. Videla, 5 Norte 1035, Viña del Mar, Chile. E-mail: [email protected]
0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2004.09.011
© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710
1574
Transplantation Proceedings, 37, 1574 –1576 (2005)
HEPATOXICITY AND CYCLOSPORINE MONITORING due to an AUC of 3 points; group A; n ⫽ 15) or by C2 values (group B, n ⫽ 23). We excluded patients with primary graft, nonfunction, pregnancy, children, and those who did not receive ketoconazole. Table 1 describes the demographics and outcomes during both monitoring periods. Immunosuppressive drugs administered included Neoral, prednisone, and azathioprine. Neoral was given as a single morning dose starting at 8 mg/kg immediately prior to transplantation and adjusted afterward to achieve either C0 ⫽ 350 to 550 ng/mL or C2 ⫽ 1200 to 1500 ng/mL during the first month posttransplant. Prednisone was tapered by 10 mg weekly until reaching 0.12 mg/kg. Azathioprine was administered at a dose of 2 mg/kg daily and ketoconazole (200 mg morning doses daily). CsA blood level determinations were performed using a nonspecific commercial radioimmunoassay kit immediately pretransplant and adjusted to achieve C0 ⫽ 350 to 550 ng/mL and C2 ⫽ 1200 to 1500 ng/mL during the first month. A three-point AUC was calculated using the 1-, 2-, and 6-hour blood levels (according a formula obtained by numeric integration). Patients had their liver enzymes evaluated prior to starting ketoconazole administration and at 3 weeks posttransplantation. Hepatobiliary echotomography, CMV antigenemia, RNA HCV detection by PCR, and HBV surface antigen were performed, whenever hepatic damage was suspected. CsA levels were monitored weekly during the first 3 months and then every other month until month 6. Statistical evaluation was performed using an unpaired onetailed Student t test with Pearson correlation.
RESULTS
There were 60 C2 levels performed among group A patients and 596 group B recipients. During the early 2-week, posttransplant period, all levels were significantly higher among group B than group A recipients: 1292 ⫾ 466 versus 573 ⫾ 249 ng/mL and 1148 ⫾ 328 versus 455 ⫾ 145 respectively. From the 6th week through the 4th and/or the 6th month this levels were 966 ⫾ 489 versus 409 ⫾ 118 ng/mL (P ⬍ .01). There was a highly significant increase in the CsA dose per kilogram comparing the 2000 to 2001 periods (9.9 ⫾ 1.87 mg/kg during the first posttransplant day) 1998 to 1999 (5.3 ⫾ 1.9 mg/kg) (P ⬍ .01). Furthermore at the 14th posttransplant day in the 2000 to 2002 period the dose was 11.5 ⫾ 1.66 mg/kg When ketoconazole was introduced there was also an increased CsA dose (over 30%) during the same time periods from 1.4 ⫾ 0.5 mg/kg to 1.83 ⫾ 0.29 (P ⬍ .01). The reason was a trend to raise CsA drug exposure to prevent acute rejections during the highest risk time immediately posttransplant period. Six patients in group B but none in group A showed altered liver function tests. All these subjects displayed elevated transaminase levels and three of them also had severe jaundice, with one patient achieving a serum bilirubin level of 12.87 mg/dL. Liver toxicity occurred between the 4th and 21st posttransplant days. The CsA dose was clearly related to the C2 value and the oxaloacetic transaminase serum levels (r2: 0.36, P ⬍ .05). Ketoconazole was discontinued when liver toxicity was suspected, after excluding other causes for liver enzyme changes, including cho-
1575 Table 1. Characteristics of Adult Renal Recipients Immunosuppressed With Cyclosporine Plus Ketoconazole in Different Time Periods 1998–1999
n Age (years) Donor (Cadaver) Sex (M/F) Time on dialysis (months) Cold ischemia time (hours) HLA Compatibility B DR MM B DR Serum creatinine (mg/dL) 3 months 1 year 2 year
2000–2002
15 42 ⫾ 10.7 15 8/7 42 ⫾ 11
23 36.7 ⫾ 13 21 12/11 52.64 ⫾ 31.3
21.5 ⫾ 5
20.2 ⫾ 4.4
1.9 ⫾ 0.8 0.9 ⫾ 0.6 1998
1999
2.34 ⫾ 0.85 1.1 ⫾ 0.4 2000–02
1.25 ⫾ 0.24 1.3 ⫾ 0.28 1.3 ⫾ 0.23
1.68 ⫾ 0.22 1.77 ⫾ 0.58 1.66 ⫾ 0.61
1.59 ⫾ 0.57 1.48 ⫾ 0.42 1.49 ⫾ 0.34
lestasis, biliary flow obstruction, or viral infection (CMV, HCV, HBV). When the CsA dose was reduced, the serum transaminase, gammaglutamyl transpeptidase, and bilirrubin levels normalized within 15 to 55 days. Following CsA dose reduction one patient required a switch from azathioprine to mycophenolate mophetil due to increased rejection risk. Ketoconazole was subsequently reincorporate namely at 12 to 120 days in all patients, except for one 65 years of age, who was kept only on steroids and low-dose CsA. Follow-up controls of these patients did not show any toxicity complications. Renal function remained stable in both groups during the first year of follow-up. Nevertheless, patients in group B, monitored using C2, showed a trend, albeit not statistically significant, toward poorer graft function than those in group A during the first year posttransplant. DISCUSSION
Early in the 1980s it had been suggested that CsA and ketoconazole could be used together only with extreme caution and with regular CsA blood level measurements.10 The CsA toxicity profiles in patients monitored using C2 blood levels have been reported to show less renal and neurological toxicity, while liver toxicity has been reported to be rare using either C0 or C2 to monitor CSA levels. AUC is the most accurate predictor of CsA immunosuppression. It correlates well with acute cellular rejection and graft loss at 1 year post–renal transplant. In our patients, AUC was higher among patients with hepatotoxicity. None experienced acute rejection episodes. We do not have any explanation for the liver toxicity without nephrotoxicity in our patients. In previous communications2– 4 we did not observe any evidence of altered liver function tests. However, when we used higher CsA doses coadministered with
1576
ketoconazole at AUC above 5500 to 6000 ng h/mL range, cholestasis disorder appeared associated with conjugated hiperbilirubinemia and moderate hepatic cytosolic enzyme elevations. Likewise, elevated CsA C2 levels recommended during the first month11,12 cannot be validated in patients taking ketoconazole, because C2 values over 1500 to 1700 ng/mL lead to liver toxicity, requiring CsA dose reduction (and in more severe cases, discontinuation of ketoconazole). It is clear that ketoconazole flattens the CsA AUC. Thus C2 levels are no longer representative of the AUC exposure. Thus, use of C2 to monitor patients treated with CsA plus ketoconazole will mean a risk of CsA overexposure and toxicity as seen in our patients. REFERENCES 1. Kowdley K, Keeffe E: Gastroenterology Clinics of North America 24:991, 1995
VIDELA, VEGA, AND BORJA 2. Foradori A, Mezzano S, Videla C, et al: Transplant Proc 30:1685, 1998 3. Videla C, Vega J, Borja H, et al: Rev Med Chile 125:438, 1997 4. Vega J, Videla C, Borja H, et al: Nefrologia Latinoamericana 7:2, 2000 5. Mahalati K, Belitsky P, West K, et al: J Am Soc Nephrol 12:823, 2001 6. Wolf A, Trendelemburg C, Diez Hernandez P, et al: Transplant Proc 26:2912, 1994 7. Galán A, Fernéndez E, Morán D, et al: Clin Exp Pharmacolo Physiol 22:260, 1995 8. Horina J, Wirnsberger G, Kenner L, et al: Transplantation 56:1091, 1993 9. Lee W: N Engl J Med 349:474, 2003 10. White D, Blatchford N, Cauwenbergh G: Transplantation 37:214, 1984 11. Levy G: Transplant Proc 31:1654, 1999 12. Mahan N, Cardella C, Cattran D, et al: Transplant Proc 33:3098, 2001