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Sirolimus monotherapy in nephrotoxicity due to calcineurin inhibitors in liver transplant recipients
ORIGINAL ARTICLES
Sirolimus Monotherapy in Nephrotoxicity Due to Calcineurin Inhibitors in Liver Transplant Recipients Satheesh Nair,* James Eason,† and George Loss† Sirolimus, being nonnephrotoxic, is a viable alternative in patients who develop renal insufficiency caused by calcineurin inhibitors (CIs). The aim of this study is to determine whether there is improvement in renal function in liver transplant recipients after switching to sirolimusbased immunosuppression. In this retrospective review, patients who were more than 3 years posttransplantation were selected. Patients who had proteinuria (protein > 300 mg/24 hr), those administered any other nephrotoxic agents, and those with a creatinine clearance (CCr) less than 20 mL/min were excluded. Renal insufficiency was defined as mild (CCr > 70 mL/min), moderate (CCr, 40 to 70 mL/min), or severe (CCr, 20 to 40 mL/min). In the 16 patients studied; there was significant improvement in serum blood urea nitrogen (36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P ⴝ .002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P ⴝ .001) 6 months after switching to sirolimus therapy. There also was a trend in improvement in CCr from 43 mL min (range, 24 to 68 mL/min) to 49 mL/min (range, 22 to 152 mL/min). Among 9 patients with moderate renal insufficiency, 2 patients improved to mild renal insufficiency, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency. Among 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency, 4 patients improved to moderate renal insufficiency, and 2 patients remained unchanged. No patient developed cellular rejection or other graft-related complications. In liver transplant recipients with chronic renal insufficiency, conversion to sirolimus-based immunosuppression allows complete withdrawal of CIs, leading to some improvement in renal function. (Liver Transpl 2003;9:126-129.)
O
verall survival after liver transplantation has improved during the last several years, with the majority of patients living well beyond 5 years.1,2 Prolonged use of both tacrolimus and cyclosporine leads to renal insufficiency, which, in some patients, ultimately progresses to end-stage renal failure requiring dialysis therapy or renal transplantation.3-6 The incidence of end-stage renal disease increases with time after transplantation, and at 13 years, the incidence is as high as 9.5%.4 Long-term survival of patients with end-stage renal disease requiring hemodialysis therapy is low, with a reported survival rate of only 27% at 6 years.7 In addition, liver transplant recipients undergoing renal retransplantation have a lower survival compared with patients undergoing primary renal transplantation.7 Sirolimus, a newer immunosuppressive drug, has been used in solid-organ recipients.8 Less nephrotoxic than calcineurin inhibitors (CIs),9-11 sirolimus is a potential alternative agent in patients who develop renal insufficiency caused by CIs. However, the efficacy of this approach in reversing chronic renal insufficiency caused by prolonged use of CIs remains unproven. Hence, the aim of our study is to determine whether switching to sirolimus-based immunosuppression leads to an improvement in renal function in liver transplant recipients with chronic renal insufficiency.
Methods Definitions
From *Gastroenterology and Hepatology and †Abdominal Organ Transplantation, Ochsner Clinic Foundation, New Orleans, LA. Presented in part at the American Association for the Study of Liver Diseases (Digestive Disease Week) Meeting, San Francisco, CA, May 19-22, 2002. Address reprint requests to Satheesh Nair, MD, Ochsner Clinic Foundation, 1514 Jefferson Hwy, BH 309, New Orleans, LA 70121. Telephone: 504-842-6353; FAX: 504-842-6599; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0902-0004$35.00/0 doi:10.1053/jlts.2003.50026
126
As a standard practice, all patients in our institution had 24-hour creatinine clearance (CCr) measured every 6 months to a year after the first year of transplantation to monitor CI nephrotoxicity. Because CCr measured from 24-urine creatinine concentration is a more accurate reflection of glomerular filtration rate than serum creatinine level, renal insufficiency in this study was defined based on CCr. An arbitrary classification was used to categorize renal insufficiency. CCr greater than 70 mL/min was considered mild renal insufficiency. Renal insufficiency was classified further as moderate if CCr was between 40 and 70 mL/min and severe if CCr was between 20 and 40 mL/min. An increase in CCr from one group to another (i.e., severe to moderate or moderate to mild) was considered an improvement in renal function with sirolimus.
Liver Transplantation, Vol 9, No 2 (February), 2003: pp 126-129
Sirolimus Salvage Therapy for Renal Toxicity
Patient Selection Data were extracted from the database for liver transplant recipients who were switched to sirolimus-based immunosuppression therapy whenever patients developed complications caused by CIs. Because our aim is to study the efficacy of sirolimus to reverse nephrotoxicity caused by long-term use of CIs, we selected patients who had been on either cyclosporine or tacrolimus therapy for at least 3 years before they were switched to sirolimus therapy. The following patients were excluded: (1) those who had evidence of cirrhosis (histologically and/or clinically) from recurrent disease in the allograft, (2) those with a 24-hour measured CCr less than 20 mL/min, (3) those with 24-hour urine protein more than 300 mg, and (4) patients administered such nephrotoxic agents as nonsteroidal anti-inflammatory agents or nephrotoxic antibiotics during the period between the two 24-hour CCr estimations. We identified 23 patients who satisfied these criteria.
Immunosuppression Doses of sirolimus were as follows: all patients had a loading dose of 5 mg on day 1, followed by 2 mg/d. A trough level was measured at 2 to 3 weeks, and a level of 5 to 10 ng/mL was considered therapeutic. The dose was reduced or increased in increments of 1 mg/d if the level was greater than 10 ng/mL or less than 5 ng/mL, respectively. The CI was discontinued after a week. Patients administered azathioprine (n ⫽ 1), prednisone (n ⫽ 1), or mycophenolate mofetil (n ⫽ 1) were continued without adjustment of doses. Liver function tests were monitored every 3 months. Because hyperlipidemia is a known side effect of sirolimus, all patients had a lipid profile performed at 6-month intervals.
Analysis Pretreatment and posttreatment serum creatinine levels and CCrs were compared using paired Wilcoxon’s rank-sum test. For all analyses, P less than .05 is considered significant. Statistical software used was SPSS 10.0 for Windows (SSPS Inc, Chicago, IL).
Results Twenty-three patients satisfied inclusion and exclusion criteria. Four patients had to have sirolimus therapy withdrawn because of mouth ulcers, and two patients developed rapidly progressive renal insufficiency (within 2 weeks; one patient had diabetic nephropathy by electron microscopy, and the other patient had community-acquired pneumonia and developed sepsis-induced renal insufficiency). One patient had inadvertently continued tacrolimus therapy for 8 weeks and was not included in the analysis. Among the remaining 16 patients (mean age, 56 ⫾ 12 years; 8 women, 8 men), 9 patients had moderate renal insufficiency (CCr, 40 to 70 mL/min) and 7
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patients had severe renal insufficiency (CCr, 20 to 40 mL/min). Median serum creatinine level was 1.95 mg/dL (range, 1.4 to 2.8 mg/dL), and mean CCr was 43 mL/min (range, 24 to 68 mL/min). Reasons for transplantation were hepatitis C (4 patients), alcoholic cirrhosis (4 patients), primary biliary cirrhosis (3 patients), primary sclerosing cholangitis (2 patients), hepatitis B (1 patient), Budd Chiari (1 patient), and carcinoid syndrome (1 patient). Liver function test results were as follows: serum albumin, 3.6 ⫾ 0.35 g/dL; serum bilirubin, 0.9 ⫾ 0.35 mg/dL; serum aspartate aminotransferase, 37 ⫾ 25 IU/L; and serum alanine aminotransferase, 34 ⫾ 22 IU/L. All patients had normal serum creatinine levels before transplantation and in the immediate posttransplantation period. Nine patients were on cyclosporine therapy, and 7 patients were on tacrolimus therapy. Mean time from liver transplantation was 8 years (minimum, 4 years; maximum, 14 years). At the time of conversion to sirolimus therapy, mean tacrolimus and cyclosporine levels were 6.4 and 102 ng/mL, respectively. There was significant improvement in serum blood urea nitrogen (median, 36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P ⫽ .002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P ⫽ .001) at 6 months after switching to sirolimus therapy (Table 1). There also was a trend in improvement of median CCr from 43 mL/min; range, 24 to 68 mL/min; to 49 mL/min; range, 22 to 152 mL/min; P ⫽ not significant) at 6 months to a year (median, 8 months). Changes in follow-up of CCrs in patients with moderate and severe renal insufficiency are shown in Figure 1. Of 9 patients with moderate renal insufficiency, CCr improved to greater than 70 mL/min in 2 patients, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency (CCr, 20 to 40 mL/min). Of 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency (CCr ⬎ 70 mL/min), 4 patients improved to moderate renal insufficiency (CCr, 40 to 70 mL/min), and 2 patients remained unchanged. Overall, 7 of 16 patients (43%) showed a significant improvement in CCr. Because 4 patients had to have sirolimus therapy withdrawn because of mouth ulcers, overall improvement in an intention-to-treat analysis was 35%. Six patients (38%) had no further deterioration in renal function. None of the patients developed clinical evidence of cellular rejection. Most patients (n ⫽ 14) could be maintained on 2 mg/d of sirolimus. There was no instance of hepatic artery thrombosis or other allograft
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Table 1. Preconversion and Postconversion Laboratory Parameters
Serum blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) CCr (mL/mn)† Serum cholesterol (mg/dL) Serum triglycerides (mg/dL)
Preconversion to Sirolimus
Postconversion to sirolimus*
P
36 (19-53) 1.95 (1.3-2.8) 43 (24-68) 172 (126-326) 154 (3-423)
25 (10-37) 1.5 (1.0-2.4) 49 (22-152) 181 (115-345) 181 (65-477)
.002 .001 NS NS .028
NOTE. N ⫽ 16. Data expressed as median (range) Abbreviation: NS; not significant. *At 6 months after starting sirolimus therapy. †At 6 months to 1 year after starting sirolimus therapy. CCr measured from 24-hour urine creatinine concentrations.
dysfunction. There was a significant increase in mean serum triglyceride levels at 6 months (median, from 154 to 181 to 162 to 225 mg/dL; P ⫽ .028) with sirolimus treatment, and one patient had a triglyceride level greater than 400 mg/dL. There was a trend to an increase in median serum cholesterol levels from 172 to 181 mg/dL at 6 months, but this was not statistically significant. Hypercholesterolemia was treated with atorvastatin (Lipitor; Parke-Davis, New York, NY). Isolated hypertriglyceridemia was treated with fenofibrate (Tricor; Abbott Laboratories, Chicago, IL).
Discussion Our study shows that sirolimus monotherapy allows safe withdrawal of CIs, leading to a significant recovery
of renal function in liver transplant recipients with chronic renal insufficiency. It also is important to note that even in patients with advanced renal insufficiency (CCr, 20 to 40 mL/min), this approach seems to improve renal function. Of 16 patients, 6 patients maintained their CCr during the observation period, which itself could represent a stabilization in renal function after withdrawal of CIs. However, our follow-up was limited to 6 months to 1 year, and as a result, it is not clear whether the beneficial effect in these patients will be sustained. In this regard, longer follow-up with monitoring of histological changes is needed to establish the long-term benefit of switching to sirolimus therapy. In our patients, we were able to maintain effective
Figure 1. Change in CCr in 16 patients at the end of 6 months to 1 year of follow-up. Renal insufficiency was classified as mild for CCr greater than 70 mL/min; moderate, for CCr between 40 and 70 mL/min; severe, for CCr between 20 and40 mL/min. and end stage, for CCr less than 20 mL/min. By our inclusion criteria, only patients with moderate or severe renal insufficiency were included. Solid arrow, results of follow-up CCr in patients with moderate renal insufficiency; broken arrow, results of follow-up CCr in patients with severe renal insufficiency. N ⴝ number of patients in each category.
Sirolimus Salvage Therapy for Renal Toxicity
immunosuppression with sirolimus monotherapy (except for the three patients also administered other medications). This probably occurred because all our patients were at least 3 years posttransplantation, and it is well known that these patients require only minimal immunosuppression. It is not clear whether this efficacy can be extrapolated to patients within the first 3 years of transplantation. A combination of sirolimus and lowdose CI deserves further study in those patients. The major side effect observed in our group of patients was mouth ulcers, despite proper precautions. All these patients were administered the liquid preparation of sirolimus, and this may not be as common with the newly marketed pills. Hyperlipidemia is a wellknown complication of sirolimus,8 and in our study, there also was a significant increase in triglyceride levels, although there was no statistically significant increase in serum cholesterol levels. However, our study is limited in terms of number of patients and duration of follow-up to properly define the risk for hyperlipidemia. Several factors can cause renal insufficiency in liver transplant recipients. In addition to CI-induced nephrotoxicity, other potential causes are diabetic nephropathy, persistence of pretransplantation renal disease,12 hepatorenal syndrome from recurrent disease in the allograft (cirrhosis from recurrent hepatitis C), and concomitant use of other nephrotoxic agents. Although we did not have histological confirmation, we are fairly confident that all our patients had CI-induced renal insufficiency because we excluded patients with proteinuria and those administered other nephrotoxic agents. In summary, conversion to sirolimus-based immunosuppression offers some benefit in improving renal insufficiency caused by CIs in liver transplant recipients, even in patients who had been on CI therapy for several years. Additional long-term studies are needed to determine whether the beneficial effect is sustained and ultimately prevent the development of end-stage renal insufficiency and improve survival.
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References 1. Sheiner PA, Magliocca JF, Bodian CA, Kim-Schluger L, Altaca G, Guarrera JV, et al. Long-term medical complications in patients surviving ⬎ or ⫽ 5 years after liver transplant. Transplantation 2000;69:781-789. 2. Jain A, Reyes J, Kashyap R, Dodson SF, Demetris AJ, Ruppert K, et al. Long-term survival after liver transplantation in 4,000 consecutive patients at a single center. Ann Surg 2000;232:490500. 3. Fisher NC, Nightingale PG, Gunson BK, Lipkin GW, Neuberger JM. Chronic renal insufficiency following liver transplantation: A retrospective analysis. Transplantation 1998;66:59-66. 4. Gonwa TA, Mai ML, Melton LB, Hays SR, Goldstein RM, Levy MF, et al. End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: Risk of development and treatment. Transplantation 2001; 72:1934-1939. 5. The US Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med 1994;331:1110-1115. 6. Platz KP, Mueller AR, Blumhardt G, Bachmann S, Bechstein WO, Kahl A, et al. Nephrotoxicity following orthotopic liver transplantation. A comparison between cyclosporine and FK506. Transplantation 1994;58:170-178. 7. Gonwa TA. Hypertension and renal dysfunction in long-term liver transplant recipients. Liver Transpl 2001;7(suppl 1):S22S26. 8. Groth CG, Backman L, Morales JM, Calne R, Kreis H, Lang P, et al. Sirolimus (sirolimus)-based therapy in human renal transplantation: Similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036-1042. 9. Chang GJ, Mahanty HD, Quan D, Freise CE, Ascher NL, Roberts JP, et al. Experience with the use of sirolimus in liver transplantation—Use in patients for whom calcineurin inhibitors are contraindicated. Liver Transpl 2000;6:734-740. 10. Kahan BD, Stepkowski SM, Napoli KL, Katz SM, Knight RJ, Van Buren C. The development of sirolimus: The University of Texas-Houston experience. Clin Transpl 2000:145-158. 11. Pescovitz MD, Govani M. Sirolimus and mycophenolate mofetil for calcineurin-free immunosuppression in renal transplant recipients. Am J Kidney Dis 2001;38(suppl 2):S16-S21. 12. Crawford DH, Endre ZH, Axelsen RA, Lynch SV, Balderson GA, Strong RW, et al. Universal occurrence of glomerular abnormalities in patients receiving liver transplants. Am J Kidney Dis 1992;19:339-344.
Sirolimus Monotherapy in Nephrotoxicity Due to Calcineurin Inhibitors in Liver Transplant Recipients Satheesh Nair,* James Eason,† and George Loss† Sirolimus, being nonnephrotoxic, is a viable alternative in patients who develop renal insufficiency caused by calcineurin inhibitors (CIs). The aim of this study is to determine whether there is improvement in renal function in liver transplant recipients after switching to sirolimusbased immunosuppression. In this retrospective review, patients who were more than 3 years posttransplantation were selected. Patients who had proteinuria (protein > 300 mg/24 hr), those administered any other nephrotoxic agents, and those with a creatinine clearance (CCr) less than 20 mL/min were excluded. Renal insufficiency was defined as mild (CCr > 70 mL/min), moderate (CCr, 40 to 70 mL/min), or severe (CCr, 20 to 40 mL/min). In the 16 patients studied; there was significant improvement in serum blood urea nitrogen (36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P ⴝ .002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P ⴝ .001) 6 months after switching to sirolimus therapy. There also was a trend in improvement in CCr from 43 mL min (range, 24 to 68 mL/min) to 49 mL/min (range, 22 to 152 mL/min). Among 9 patients with moderate renal insufficiency, 2 patients improved to mild renal insufficiency, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency. Among 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency, 4 patients improved to moderate renal insufficiency, and 2 patients remained unchanged. No patient developed cellular rejection or other graft-related complications. In liver transplant recipients with chronic renal insufficiency, conversion to sirolimus-based immunosuppression allows complete withdrawal of CIs, leading to some improvement in renal function. (Liver Transpl 2003;9:126-129.)
O
verall survival after liver transplantation has improved during the last several years, with the majority of patients living well beyond 5 years.1,2 Prolonged use of both tacrolimus and cyclosporine leads to renal insufficiency, which, in some patients, ultimately progresses to end-stage renal failure requiring dialysis therapy or renal transplantation.3-6 The incidence of end-stage renal disease increases with time after transplantation, and at 13 years, the incidence is as high as 9.5%.4 Long-term survival of patients with end-stage renal disease requiring hemodialysis therapy is low, with a reported survival rate of only 27% at 6 years.7 In addition, liver transplant recipients undergoing renal retransplantation have a lower survival compared with patients undergoing primary renal transplantation.7 Sirolimus, a newer immunosuppressive drug, has been used in solid-organ recipients.8 Less nephrotoxic than calcineurin inhibitors (CIs),9-11 sirolimus is a potential alternative agent in patients who develop renal insufficiency caused by CIs. However, the efficacy of this approach in reversing chronic renal insufficiency caused by prolonged use of CIs remains unproven. Hence, the aim of our study is to determine whether switching to sirolimus-based immunosuppression leads to an improvement in renal function in liver transplant recipients with chronic renal insufficiency.
Methods Definitions
From *Gastroenterology and Hepatology and †Abdominal Organ Transplantation, Ochsner Clinic Foundation, New Orleans, LA. Presented in part at the American Association for the Study of Liver Diseases (Digestive Disease Week) Meeting, San Francisco, CA, May 19-22, 2002. Address reprint requests to Satheesh Nair, MD, Ochsner Clinic Foundation, 1514 Jefferson Hwy, BH 309, New Orleans, LA 70121. Telephone: 504-842-6353; FAX: 504-842-6599; E-mail: [email protected] Copyright © 2003 by the American Association for the Study of Liver Diseases 1527-6465/03/0902-0004$35.00/0 doi:10.1053/jlts.2003.50026
126
As a standard practice, all patients in our institution had 24-hour creatinine clearance (CCr) measured every 6 months to a year after the first year of transplantation to monitor CI nephrotoxicity. Because CCr measured from 24-urine creatinine concentration is a more accurate reflection of glomerular filtration rate than serum creatinine level, renal insufficiency in this study was defined based on CCr. An arbitrary classification was used to categorize renal insufficiency. CCr greater than 70 mL/min was considered mild renal insufficiency. Renal insufficiency was classified further as moderate if CCr was between 40 and 70 mL/min and severe if CCr was between 20 and 40 mL/min. An increase in CCr from one group to another (i.e., severe to moderate or moderate to mild) was considered an improvement in renal function with sirolimus.
Liver Transplantation, Vol 9, No 2 (February), 2003: pp 126-129
Sirolimus Salvage Therapy for Renal Toxicity
Patient Selection Data were extracted from the database for liver transplant recipients who were switched to sirolimus-based immunosuppression therapy whenever patients developed complications caused by CIs. Because our aim is to study the efficacy of sirolimus to reverse nephrotoxicity caused by long-term use of CIs, we selected patients who had been on either cyclosporine or tacrolimus therapy for at least 3 years before they were switched to sirolimus therapy. The following patients were excluded: (1) those who had evidence of cirrhosis (histologically and/or clinically) from recurrent disease in the allograft, (2) those with a 24-hour measured CCr less than 20 mL/min, (3) those with 24-hour urine protein more than 300 mg, and (4) patients administered such nephrotoxic agents as nonsteroidal anti-inflammatory agents or nephrotoxic antibiotics during the period between the two 24-hour CCr estimations. We identified 23 patients who satisfied these criteria.
Immunosuppression Doses of sirolimus were as follows: all patients had a loading dose of 5 mg on day 1, followed by 2 mg/d. A trough level was measured at 2 to 3 weeks, and a level of 5 to 10 ng/mL was considered therapeutic. The dose was reduced or increased in increments of 1 mg/d if the level was greater than 10 ng/mL or less than 5 ng/mL, respectively. The CI was discontinued after a week. Patients administered azathioprine (n ⫽ 1), prednisone (n ⫽ 1), or mycophenolate mofetil (n ⫽ 1) were continued without adjustment of doses. Liver function tests were monitored every 3 months. Because hyperlipidemia is a known side effect of sirolimus, all patients had a lipid profile performed at 6-month intervals.
Analysis Pretreatment and posttreatment serum creatinine levels and CCrs were compared using paired Wilcoxon’s rank-sum test. For all analyses, P less than .05 is considered significant. Statistical software used was SPSS 10.0 for Windows (SSPS Inc, Chicago, IL).
Results Twenty-three patients satisfied inclusion and exclusion criteria. Four patients had to have sirolimus therapy withdrawn because of mouth ulcers, and two patients developed rapidly progressive renal insufficiency (within 2 weeks; one patient had diabetic nephropathy by electron microscopy, and the other patient had community-acquired pneumonia and developed sepsis-induced renal insufficiency). One patient had inadvertently continued tacrolimus therapy for 8 weeks and was not included in the analysis. Among the remaining 16 patients (mean age, 56 ⫾ 12 years; 8 women, 8 men), 9 patients had moderate renal insufficiency (CCr, 40 to 70 mL/min) and 7
127
patients had severe renal insufficiency (CCr, 20 to 40 mL/min). Median serum creatinine level was 1.95 mg/dL (range, 1.4 to 2.8 mg/dL), and mean CCr was 43 mL/min (range, 24 to 68 mL/min). Reasons for transplantation were hepatitis C (4 patients), alcoholic cirrhosis (4 patients), primary biliary cirrhosis (3 patients), primary sclerosing cholangitis (2 patients), hepatitis B (1 patient), Budd Chiari (1 patient), and carcinoid syndrome (1 patient). Liver function test results were as follows: serum albumin, 3.6 ⫾ 0.35 g/dL; serum bilirubin, 0.9 ⫾ 0.35 mg/dL; serum aspartate aminotransferase, 37 ⫾ 25 IU/L; and serum alanine aminotransferase, 34 ⫾ 22 IU/L. All patients had normal serum creatinine levels before transplantation and in the immediate posttransplantation period. Nine patients were on cyclosporine therapy, and 7 patients were on tacrolimus therapy. Mean time from liver transplantation was 8 years (minimum, 4 years; maximum, 14 years). At the time of conversion to sirolimus therapy, mean tacrolimus and cyclosporine levels were 6.4 and 102 ng/mL, respectively. There was significant improvement in serum blood urea nitrogen (median, 36 mg/dL; range, 19 to 53 mg/dL; to 25 mg/dL; range, 10 to 37 mg/dL; P ⫽ .002) and serum creatinine levels (median, 1.95 mg/dL; range, 1.3 to 2.8 mg/dL; to 1.5 mg/dL; range, 1.0 to 2.4 mg/dL; P ⫽ .001) at 6 months after switching to sirolimus therapy (Table 1). There also was a trend in improvement of median CCr from 43 mL/min; range, 24 to 68 mL/min; to 49 mL/min; range, 22 to 152 mL/min; P ⫽ not significant) at 6 months to a year (median, 8 months). Changes in follow-up of CCrs in patients with moderate and severe renal insufficiency are shown in Figure 1. Of 9 patients with moderate renal insufficiency, CCr improved to greater than 70 mL/min in 2 patients, 4 patients remained unchanged, and 3 patients deteriorated to severe renal insufficiency (CCr, 20 to 40 mL/min). Of 7 patients with severe renal insufficiency, 1 patient improved to mild renal insufficiency (CCr ⬎ 70 mL/min), 4 patients improved to moderate renal insufficiency (CCr, 40 to 70 mL/min), and 2 patients remained unchanged. Overall, 7 of 16 patients (43%) showed a significant improvement in CCr. Because 4 patients had to have sirolimus therapy withdrawn because of mouth ulcers, overall improvement in an intention-to-treat analysis was 35%. Six patients (38%) had no further deterioration in renal function. None of the patients developed clinical evidence of cellular rejection. Most patients (n ⫽ 14) could be maintained on 2 mg/d of sirolimus. There was no instance of hepatic artery thrombosis or other allograft
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Table 1. Preconversion and Postconversion Laboratory Parameters
Serum blood urea nitrogen (mg/dL) Serum creatinine (mg/dL) CCr (mL/mn)† Serum cholesterol (mg/dL) Serum triglycerides (mg/dL)
Preconversion to Sirolimus
Postconversion to sirolimus*
P
36 (19-53) 1.95 (1.3-2.8) 43 (24-68) 172 (126-326) 154 (3-423)
25 (10-37) 1.5 (1.0-2.4) 49 (22-152) 181 (115-345) 181 (65-477)
.002 .001 NS NS .028
NOTE. N ⫽ 16. Data expressed as median (range) Abbreviation: NS; not significant. *At 6 months after starting sirolimus therapy. †At 6 months to 1 year after starting sirolimus therapy. CCr measured from 24-hour urine creatinine concentrations.
dysfunction. There was a significant increase in mean serum triglyceride levels at 6 months (median, from 154 to 181 to 162 to 225 mg/dL; P ⫽ .028) with sirolimus treatment, and one patient had a triglyceride level greater than 400 mg/dL. There was a trend to an increase in median serum cholesterol levels from 172 to 181 mg/dL at 6 months, but this was not statistically significant. Hypercholesterolemia was treated with atorvastatin (Lipitor; Parke-Davis, New York, NY). Isolated hypertriglyceridemia was treated with fenofibrate (Tricor; Abbott Laboratories, Chicago, IL).
Discussion Our study shows that sirolimus monotherapy allows safe withdrawal of CIs, leading to a significant recovery
of renal function in liver transplant recipients with chronic renal insufficiency. It also is important to note that even in patients with advanced renal insufficiency (CCr, 20 to 40 mL/min), this approach seems to improve renal function. Of 16 patients, 6 patients maintained their CCr during the observation period, which itself could represent a stabilization in renal function after withdrawal of CIs. However, our follow-up was limited to 6 months to 1 year, and as a result, it is not clear whether the beneficial effect in these patients will be sustained. In this regard, longer follow-up with monitoring of histological changes is needed to establish the long-term benefit of switching to sirolimus therapy. In our patients, we were able to maintain effective
Figure 1. Change in CCr in 16 patients at the end of 6 months to 1 year of follow-up. Renal insufficiency was classified as mild for CCr greater than 70 mL/min; moderate, for CCr between 40 and 70 mL/min; severe, for CCr between 20 and40 mL/min. and end stage, for CCr less than 20 mL/min. By our inclusion criteria, only patients with moderate or severe renal insufficiency were included. Solid arrow, results of follow-up CCr in patients with moderate renal insufficiency; broken arrow, results of follow-up CCr in patients with severe renal insufficiency. N ⴝ number of patients in each category.
Sirolimus Salvage Therapy for Renal Toxicity
immunosuppression with sirolimus monotherapy (except for the three patients also administered other medications). This probably occurred because all our patients were at least 3 years posttransplantation, and it is well known that these patients require only minimal immunosuppression. It is not clear whether this efficacy can be extrapolated to patients within the first 3 years of transplantation. A combination of sirolimus and lowdose CI deserves further study in those patients. The major side effect observed in our group of patients was mouth ulcers, despite proper precautions. All these patients were administered the liquid preparation of sirolimus, and this may not be as common with the newly marketed pills. Hyperlipidemia is a wellknown complication of sirolimus,8 and in our study, there also was a significant increase in triglyceride levels, although there was no statistically significant increase in serum cholesterol levels. However, our study is limited in terms of number of patients and duration of follow-up to properly define the risk for hyperlipidemia. Several factors can cause renal insufficiency in liver transplant recipients. In addition to CI-induced nephrotoxicity, other potential causes are diabetic nephropathy, persistence of pretransplantation renal disease,12 hepatorenal syndrome from recurrent disease in the allograft (cirrhosis from recurrent hepatitis C), and concomitant use of other nephrotoxic agents. Although we did not have histological confirmation, we are fairly confident that all our patients had CI-induced renal insufficiency because we excluded patients with proteinuria and those administered other nephrotoxic agents. In summary, conversion to sirolimus-based immunosuppression offers some benefit in improving renal insufficiency caused by CIs in liver transplant recipients, even in patients who had been on CI therapy for several years. Additional long-term studies are needed to determine whether the beneficial effect is sustained and ultimately prevent the development of end-stage renal insufficiency and improve survival.
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