Sirolimus Conversion After Liver Transplantation: Improvement in Measured Glomerular Filtration Rate After 2 Years

Other Problems

Sirolimus Conversion After Liver Transplantation: Improvement in Measured Glomerular Filtration Rate After 2 Years E.Q. Sanchez, A.P. Martin, T. Ikegami, T. Uemura, G. Narasimhan, R.M. Goldstein, M.F. Levy, S. Chinnakotla, S. Dawson III, H.B. Randall, G. Saracino, and G.B. Klintmaim ABSTRACT Methods. We reviewed our prospectively maintained database of 2005 liver transplantations. Therapy was either started de novo or converted from calcineurin inhibitors (CNIs) to sirolimus as the main immunosuppressive agent for nephrotoxicity or rejection. Glomerular filtration rate (GFR) was determined with iodine 125–labeled sodium isthalamate (Glofil-125), and serum creatinine concentration was obtained before and 3 months after transplantation, and yearly in both groups. Sirolimus levels were 10 to 15 ng/mL in patients at less than 3 months after transplantations and 5 to 10 ng/mL in the remaining patients. All patients received mycophenolate mofetil as maintenance therapy. Results. Data for 29 patients in the de novo group and 35 in the conversion group were reviewed. Patients in the de novo group demonstrated an acute cellular rejection rate of 17.2%, 40% of which were steroid resistant. In this group, 48.2% discontinuation of sirolimus was necessary because of adverse effects. Patients in the conversion group demonstrated an acute cellular rejection rate of 2.8% and a 34.3% rate of sirolimus discontinuation. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years demonstrated continued improvement in GFR. In the conversion group, case-control analysis did not demonstrate a significant difference in GFR and serum creatinine concentration (P ⬎ .05) at 1 and 2 years after conversion. At the time of review, no patients in the conversion group required hemodialysis. Conclusions. Conversion to sirolimus therapy is an effective strategy in improving renal function in patients with CNI-induced nephrotoxicity and can be done without increased rejection. Most of our patients (65.7%) tolerated sirolimus conversion. Of these, 56.7% and 44.4% demonstrated continued increase in GFR with the CNI-free regimen at 1 and 2 years, respectively. Long-term, large-population, prospective, randomized, controlled studies should further validate these results.

S

IROLIMUS use in liver transplantation is becoming more common. Its mechanism of action and side effect profiles are distinct from calcineurin inhibitors (CNIs), and synergism with cyclosporine and tacrolimus has been identified.1 It is a powerful immunosuppressant in vitro and in animal models.2– 4 The use of sirolimus has also been shown to slow the progression of allograft vascular disease in kidneys. However, its use has not been universally accepted

in the immediate post–liver transplant period. Despite its success in renal transplantation, its use in liver transplantaFrom Transplantation Services, Baylor University Medical Center, Dallas, Texas. Address reprint requests to Edmund Q. Sanchez, MD, Transplantation Services, Baylor University Medical Center, 4 Roberts, Dallas, TX 75246. E-mail: [email protected]

0041-1345/05/$–see front matter doi:10.1016/j.transproceed.2005.10.019

© 2005 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

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Transplantation Proceedings, 37, 4416 – 4423 (2005)

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tion has been hindered because of adverse effects, mainly on wound healing,5 infection,6 dyslipidemia (more so when used with cyclosporine),7 and leukopenia8; therefore the current black box warning from the US Food and Drug Administration. Studies have confirmed that sirolimus does not impair function in renal transplant allografts. The reduction of CNI-induced diabetes and hypertension makes the use of the drug more attractive. In addition, the renal transplant rejection rates on sirolimus-only-based immunosuppression demonstrate similar or slightly increased9 incidence when compared with sirolimus plus CNI protocols.10 Also, Johnson et al10 have shown that sirolimus enables early cyclosporine withdrawal in kidney transplant recipients,10 and cyclosporine elimination is safe and can improve kidney transplant function.11 The long-term use of CNIs in liver transplantation is now more frequently manifested in chronic renal dysfunction and even in the development of (ESRD).12,13 This presents us with an opportunity to discuss an alternative and possible use for sirolimus in liver transplantation and its usefulness as an effective immunosuppressive agent with renal-sparing properties. This study retrospectively analyzes clinical data regarding its de novo use with CNI. More important, conversion from CNI-based immunosuppression therapy to sirolimus-based immunosuppression therapy is also discussed.

performed to monitor sCr concentration with the CNI minimization. In addition, iodine 125–labeled sodium iodothalamate (Glofil125) was used to establish an accurate assessment of the patient’s true glomerular filtration rate (GFR) was then performed. If the GFR was 30 to 40 mL/min or less with complete minimization of CNI use and the sCr concentration remained elevated, therapy was converted to sirolimus and mycophenolate mofetil– based immunosuppression. This included tapering CNI for approximately 7 to 14 days until an appropriate level of sirolimus was obtained. After conversion, levels of sirolimus were maintained between 10 and 15 ng/mL when used within 3 months of transplantation and between 5 and 10 ng/mL after 3 months posttransplantation. In addition, during sirolimus-based immunosuppression therapy, mycophenolate mofetil (1 g twice a day) was initiated or continued, as clinically tolerated. Institutional steroid protocols were followed (Table 1).

METHODS A review of our prospectively maintained liver transplant database of 2005 transplants from 1985 to 2002 was performed. A retrospective review of patients given sirolimus was performed. The immunosuppressive protocols used at our institution were targeted for specific populations (Table 1). In the periods when sirolimus was in its initial clinical trials for use in liver transplantation or when it was clinically approved, tacrolimus-based immunosuppression therapy was the main regimen used, except in patients with hepatocellular carcinoma, in whom cyclosporine is used. The indications for use of sirolimus at our center were mainly investigational, hepatocellular carcinoma protocol, persistent acute cellular rejection, neurotoxicity from CNI, and nephrotoxicity from CNI.

Evaluation of glomerular filtration rate and renal function Pretransplantation workup included GFR determination using both the I125 Glofil method and standard laboratory tests. Posttransplantation follow-up included blood chemistry, Glofil, and clinical follow-up. The Glofil-125 test was performed at 6 weeks after liver transplantation and before conversion to sirolimus. Serial creatinine levels were obtained through interval follow-up. Subsequently, Glofil-125 tests were performed at physician discretion as directed by worsening sCr level or by yearly follow-up protocols. The determination to convert from a CNI-based regimen to sirolimus was made when results of the Glofil-125 test were between 30 and 40 mL/min or lower. No kidney biopsies were performed in this population. The Glofil-125 and sCr data were analyzed statistically with paired data analysis.

Clinical adverse effects requiring dose adjustment or cessation of drug Clinical data related to adverse effects from sirolimus therapy were tabulated. Responses to dose changes, withdrawal from drug, and acute cellular rejection episodes were evaluated. Dose adjustment initially required halving the sirolimus dose and observation for at least 7 days. In indicated patients, sirolimus doses were decreased or discontinued for a time. Refractory cases required sirolimus withdrawal.

Immunosuppression regimen

RESULTS

The investigational use of sirolimus was during the Wyeth Ayerst 211 study and was used in combination with tacrolimus (study levels of sirolimus were 10 –20 ng/mL using the Abbott assay) and steroids. In patients with hepatocellular carcinoma or autoimmune disorders, the sirolimus doses used were typically either a 5-mg or 3-mg loading dose followed by 2 mg each day. Drug blood levels were obtained twice a week, and lipid profiles were obtained once a week until stable. Doses were adjusted per level or according to adverse effects. The conversion process and patient selection was initiated by identifying patients with rising serum creatinine (sCr) concentrations. The initial maneuver was to decrease cyclosporine to trough levels of 75 to 150 mg/mL or tacrolimus to trough levels of 3 to 5 mg/mL (as clinically tolerated). In addition, mycophenolate was maximized as tolerated. Serial laboratory determinations were then

Sixty-four patients were administered sirolimus. In 29 patients sirolimus was started immediately posttransplantation (de novo group), according to study and hepatocellular carcinoma protocols. The other 35 were on a CNI-based protocol was converted to sirolimus therapy. De Novo Group

The de novo group had a median exposure to sirolimus of 529 days (range, 4 –1566 days) before discontinuation of drug. Target sirolimus and CNI levels were maintained per study protocol. De novo use of sirolimus had an acute cellular rejection rate of 17.2% (5/29 patients). Steroid-resistant rejection requiring the use of OKT3 was seen in 2 of the 5 patients.

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Table 1. Post–Liver Transplantation Steroid and Immunosuppression Protocols Used at Baylor University Medical Center Posttransplantation Oral Prednisolone Liver Disease

Postoperative SoluMedrol

5 d–3 mo

⬎12 mo

3–12 mo

Study Protocol (SRL 211) Standard

Autoimmune

Viral hepatitis

Hepatoma

Coma, III and IV

Antibody

Notes

Tacrolimus Sirolimus Steroid Tacrolimus Steroid

May convert to sirolimus ⫹ MMF as renal function deteriorates

20 mg, day 5 15 mg, day 90

10 mg, day 180 7.5 mg, day 270 5 mg, day 360

Do not discontinue steroids

Tacrolimus Sirolimus Steroid

20 mg, day 5 15 mg, day 6 10 mg, day 7 5 mg, day 14 2.5 mg, day 30 Discontinue day 60

NA

NA

Tacrolimus MMF Steroid

20 mg, day 5 15 mg, day 14 12.5 mg, day 21 10 mg, day 28 7.5 mg, day 60 5 mg, day 90 20 mg, day 5 15 mg, day 14 12.5 mg, day 21 10 mg, day 28 7.5 mg, day 60 5 mg, day 90 20 mg, day 5 15 mg, day 14 12.5 mg, day 21 10 mg, day 28 7.5 mg, day 60 5 mg, day 90

2.5 mg, day 360

2.5 mg QOD, day 390 Discontinue, day 420

Cyclosporine Sirolimus Steroid

2.5 mg, day 360

Do not discontinue steroids

MMF or sirolimus Steroid

OKT3 or thymoglobulin

Sirolimus ⫹ MMF if no return of renal function

2.5 mg, day 360

2.5 mg QOD, day 390 Discontinue, day 420

MMF Steroid

OKT3 or thymoglobulin

Sirolimus ⫹ MMF for CNIinduced neurotoxicity

Preop, preoperative; intraop, intraoperative; IV, intravenously; SC, subcutaneously; MMF, mycophenolate mofetil; CNI, calcineurin inhibitor.

CNI minimized or discontinued because of progressive renal decline

SANCHEZ, MARTIN, IKEGAMI, ET AL

Acute renal failure

Preop: 40 mg IV Intraop: 1 g SC Day 1: 100 mg IV Day 2: 80 mg IV Day 3: 60 mg IV Day 4: 40 mg IV Preop: 40 mg IV Intraop: 200 mg IV Day 1: 100 mg IV Day 2: 80 mg IV Day 3: 60 mg IV Day 4: 40 mg IV Preop: 40 mg IV Intraop: 200 mg IV Day 1: 100 mg IV Day 2: 80 mg IV Day 3: 60 mg IV Day 4: 40 mg IV Preop: 40 mg IV Intraop: 1 g SC Day 1: 100 mg IV Day 2: 80 mg IV Day 3: 60 mg IV Day 4: 40 mg IV Preop: 40 mg IV Intraop: 1 gm SC Day 1: 100 mg IV Day 2: 80 mg IV Day 3: 60 mg IV Day 4: 40 mg IV Preop: 40 mg IV Intraop: 1 mg SC Day 1: 100 mg IV Day 2: 80 mg IV Day 3: 60 mg IV Day 4: 40 mg IV

Immunosuppression Therapy

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Table 2. Comparison of Adverse Effects in Different Sirolimus Protocols Dose Adjustment

De novo group

Conversion group

No. of Patients

Leukopenia Thrombocytopenia Wound infection Wound dehiscence Bacterial infection CMV Leukopenia Thrombocytopenia Anemia Deep venous thrombosis Bacterial infection CMV viremia Fungal infection

2 4 4 2 10 1 9 3 1 1 8 5 3

Cessation of Sirolimus

No. of Patients

Refractory hyperlipidemia Myelosuppression Hyperglycemia Infection (sepsis) Surgical wound infection Thromboses Acute cellular rejection Refractory hyperlipidemia Infection Gastrointestinal Cancer Postsurgery wound infection

1 2 1 5 1 3 1 2 6 2 1 1

Cellular Rejection

No. of Patients

Steroid responsive

3

Steroid resistant

2

Steroid sensitive

1

CMV, cytomegalovirus.

Fourteen (48.2%) complications in the de novo group required discontinuation of sirolimus (Table 2). Conversion Group

In 35 patients therapy was converted to sirolimus because of CNI neurotoxicity (n ⫽ 3), acute cellular rejection (n ⫽ 5), and nephrotoxicity (n ⫽ 27). The median time to initiating sirolimus from time of transplantation was 177.5 days (range, 4 – 4534). The median exposure time was 380 days (range, 4 –1969). Calcineurin inhibitor–induced neurotoxicity was found in 3 patients. In 2 of the 3 patients there was complete disappearance of neurotoxicity after conversion to sirolimus therapy. The third patient died in coma, and therefore neurologic assessment could not be assessed. Acute cellular rejection refractory to CNI optimization and adjuvant treatment (supplemental steroid recycle) was the indication in 5 patients. These 5 patients received a maintenance triple-drug regimen (sirolimus, mycophenolate mofetil, and prednisolone) after the acute cellular rejection episode. Nephrotoxicity defined by Glofil-125, 30 to 40 mL/min or less during CNI therapy was noted in the remaining 27 patients. Conversion to sirolimus demonstrated only one episode of acute cellular rejection. There were no episodes of steroid-resistant rejection. Twelve (34.3%) patients in the conversion group required sirolimus discontinuation (Table 2). Glofil-125 and Serum Creatinine Concentration

In 32 patients (16 men, 16 women), with mean age at liver transplantation of 50.3 ⫾ 12.8 years, therapy was converted to sirolimus, because of nephrotoxicity in 27 patients and acute rejection in 5 patients. Glomerular filtration rate (Fig. 1) and sCr data were accumulated. There were 30 patients at 1 year, 18 patients at 2 years, and 5 patients at 3 years. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years exhibited stable or continued improvement in

GFR. In addition, 8 (26.7%) patients at 1 year and 5 (27.8%) patients at 2 years showed progressive decline in GFR. At the time of review, no patients required hemodialysis. Case-control analysis was based on age, sCr, and liver disease. The GFR and sCr data are given in Table 3. There was no significant difference in age. In the conversion group, there was a 61.3% decline in GFR from pretransplantation to time of conversion. This improved to a 51% decline in GFR at 3 months after conversion. This is compared with a case-control 23% GFR decrease in the 3-month period posttransplantation (P ⫽ .05). However, the Glofil-125 results improved at later follow-ups (Fig. 2). One-year and 2-year GFR values were 55.4 mL/min and 51.2 mL/min in case-control subjects, compared with 53.9 mL/min and 49.8 mL/min (P ⫽ NS at both time points) in the conversion group. Serum creatinine (Fig. 3) data only show a significant difference (P ⫽ .02) at 2 years after conversion (1.8 ⫾ 0.6) compared with case-control subjects (1.4 ⫾ 0.4). DISCUSSION

Liver transplantation has entered its golden era as reflected by the high rates of success with long-term patient and graft survival. The success has been mainly due to the use of CNI-based immunosuppressive regimens, the development of other potent immunosuppressant agents (eg, mycophenolate mofetil, daclizumab, basiliximab), clinical management, surgical technique, and stringent recipient selection criteria. However, with success comes a price. Though liver graft function and survival may remain at excellent levels years after transplantation, renal function most likely will show decline. Renal function after liver transplantation is one of the significant predictors of morbidity and mortality.14,15 Almost coincident with long-term use of CNI is chronic renal dysfunction and end-stage renal disease.16 A review from our institution by Gonwa et al16 demonstrated that ESRD that developed in 73.3% of patients after liver transplanta-

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SANCHEZ, MARTIN, IKEGAMI, ET AL

Fig 1. Glofil-125 measurements in patients converted to sirolimus therapy.

tion was due to CNI. Perhaps the simplest solution to reduce the incidence of ESRD caused by CNI protocols is to avoid them or to minimize them. Minimization protocols are successful to a certain extent; however, the offending agent is still deemed essential.17 Calcineurin-free protocols, though population sizes are small, are also being evaluated; however, they demonstrate high rates of early rejection.18 The use of sirolimus has been convincingly studied in the kidney transplant literature. Its use has been highly successful. The benefits of sirolimus are that it is not a CNI and does not demonstrate nephrotoxicity. In addition, it does not demonstrate adverse effects such as hypertension or induction of diabetes mellitus. Studies have shown that calculated GFR can improve with use of sirolimus alone.10 Infection rates and other long-term use complications do not exceed those with CNI. In addition, the use of sirolimus has an antiproliferative effect demonstrated in the fibroblast population and also in hepatocellular carcinoma cell lines. In liver transplantation, the use of sirolimus has been heralded with outcomes that were less than desirable.

Complications such as wounds, infections, vascular thromboses, and delayed healing hinder the progress of sirolimus therapy in liver transplantation. However, more literature has been published that show sirolimus to be an effective immunosuppressive agent with comparable rates of adverse effects compared with CNI.19 In addition, new uses for the drug have been identified, especially its use as an antitumor agent in hepatocellular carcinoma, antifibrinogenesis in vivo,20 and also as an antiatherogenic agent, and it is thought to have a role in tolerance induction. Perhaps the most important benefit with the use of sirolimus is its renal-sparing ability, therefore making this drug an attractive long-term alternative to CNI as maintenance immunosuppression therapy. Renal failure in the long-term surviving liver transplantation population has recently become an even more significant issue involving survival and quality of life. The longterm rate of renal failure and chronic renal failure at our center is 14.4%. Other centers demonstrate chronic renal failure rates of 3.4% to 28%.21–23 Previous studies24 deter-

Table 3. Glomerular Filtration and Serum Creatinine Case-Control Analysis Time

GFR (control)

GFR (SRL)

sCr (control)

sCr (SRL)

P (vs case-control)

Pretransplantation Preconversion 3 mo 1y 2y

77 ⫾ 24.7 N/A 59.6 ⫾ 26.6ⴱ 55.4 ⫾ 27.8 51.2 ⫾ 23.7

84.7 ⫾ 49.2 33.7 ⫾ 17.2 41.9 ⫾ 26.1ⴱ 53.9 ⫾ 26.2 49.8 ⫾ 22.9

1.5 ⫾ 1.0 N/A 1.5 ⫾ 0.6 1.7 ⫾ 0.6 1.4 ⫾ 0.4ⴱ

1.9 ⫾ 1.5 1.8 ⫾ 1.6 1.7 ⫾ 1.2 1.8 ⫾ 1.2 1.8 ⫾ 0.6ⴱ

NS NS ⴱP ⫽ .05 NS ⴱP ⫽ .02

GFR, glomerular filtration rate; SRL, sirolimus; sCr, serum creatinine concentration.

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Fig 2. Glomerular filtration rate (GFR) comparison between case-control group and sirolimus conversion group.

mined that there was a 30% to 40% reduction in GFR within the first 6 months and that reduction occurred mostly in the first 3 to 4 weeks, with stabilization over the next 4 to 5 years. However, the survival periods have now exceeded the 5-year follow-up, and we are seeing trends toward the development of chronic renal failure and ESRD. Liver transplant recipients in whom ESRD requiring hemodialysis develop have a 27% survival rate at 6 years on hemodialysis.16 In addition, these patients will have worse survival than those with a kidney as their only transplant. Therefore, it seems more than reasonable to use a drug without long-term nephrotoxicity. This study shows that sirolimus is the agent that will be renal protective over the long-term. It offers immunosuppressive coverage comparable to that with CNI, and based on our limited follow-up, the transition can be made to sirolimus quite effectively with a trivial incidence of rejection. Conver-

sion to sirolimus was performed at a median of 177.5 days after liver transplantation in this study, a relatively immunologically stable time point after transplant. In any event, we believe that conversion because of renal insufficiency and neurotoxicity is safe when timed appropriately. Not all patients in this study benefited from conversion to sirolimus. The GFR data demonstrated that some patients did not respond or declined despite conversion. This may have been due to other unidentified causes and factors that are involved with irreversible declining GFR after liver transplantation. In addition, this can lead us to hypothesize that there may be a “critical” level of GFR. If conversion is performed below this level, then there would be no possible renal-sparing benefit with conversion to sirolimus, and perhaps this could be an indication for renal biopsy to assist with prognosis. However, we have a few patients that had GFRs in the range of 20 to

Fig 3. Serum creatinine (sCr) comparison between case-control group and sirolimus conversion group.

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30 mL/min who demonstrated improvement with the sirolimus protocol. Improvement continued into the second year of follow-up. The use of measured GFR in this study validates the renal protective ability of sirolimus. As seen in our data and those of others, sCr is not a good marker of true renal function. Subsequently, calculated creatinine clearance is also of no value. Surrogate markers of GFR such as serum cystatin C25 may be more beneficial in detecting early decline in glomerular filtration over extended periods.26 It has been shown to be useful in detecting abnormal glomerular filtration in patients with normal creatinine concentration after liver transplantation.27 Since it is a blood test, it is less labor intensive and more patient friendly. Cystatin C has also been more highly correlated with iohexol clearance methods of glomerular filtration determination.28 Nonetheless, supplemental confirmation of actual GFR is of extreme importance after liver transplantation. Serial GFR determinations with the Glofil-125 method or equivalent (iohexol, inulin, iodothalamate) must be performed. The timing of the use of sirolimus is seen to be optimal when it is not in the acute postoperative phase of liver transplantation. Data for the de novo group demonstrated a 48% discontinuation rate vs 34.3% in the conversion group. Acute cellular rejection in 17.2% of patients in the de novo group vs 2.7% in the conversion group also leads us to believe that the use of sirolimus is not indicated in the immediate period after liver transplantation. We did not observe profound myelosuppressive effects that both mycophenolate and sirolimus individually exhibit. We report very low numbers of thrombocytopenia and leukopenia, which responded to drug dose changes and was not an indication for drug cessation in the conversion group. Other adverse effects and their long-term effects after liver transplantation were not evaluated statistically in this study. Sirolimus is an excellent alternative immunosuppressive agent for long-term use in liver transplant recipients. The conversion was not associated with higher rates of acute cellular rejection, either in the conversion period or the maintenance period afterward. Our 2-year follow-up data show that most patients in whom CNI therapy is converted to sirolimus will regain GFR to match the case-control at 1 and 2 years postconversion. Although there was a small number of patients in the postconversion group whose GFR progressively declined, we have demonstrated that in the others GFR is maintained or continues to improve throughout the follow-up period. Finally, at the time of this writing, no patients in the conversion group have required hemodialysis. REFERENCES 1. Kahan BD: Cyclosporin A, FK506, rapamycin: the use of a quantitative analytic tool to discriminate immunosuppressive drug interactions. J Am Soc Nephrol 2(suppl):S222, 1992

SANCHEZ, MARTIN, IKEGAMI, ET AL 2. Calne RY, Collier DS, Lim S, et al: Rapamycin for immunosuppression in organ allografting. Lancet 2:227, 1989 3. Collier DS, Calne R, Thiru S, et al: Rapamycin in experimental renal allografts in dogs and pigs. Transplant Proc 22:1674, 1990 4. Collier DS, Calne RY, Pollard SG, et al: Rapamycin in experimental renal allografts in primates. Transplant Proc 23:2246, 1991 5. Guilbeau JM: Delayed wound healing with sirolimus after liver transplant. Ann Pharmacother 36:1391, 2002 6. Morelon E, Stern M, Israel-Biet D, Correas JM, et al: Characteristics of sirolimus-associated interstitial pneumonitis in renal transplant patients. Transplantation 72:787, 2001 7. Trotter JF, Wachs ME, Trouillot TE, et al: Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Liver Transplant 7:401, 2001 8. Groth CG, Backman L, Morales JM, et al: Sirolimus (rapamycin)– based therapy in human renal transplantation: similar efficacy and different toxicity compared with cyclosporine. Sirolimus European Renal Transplant Study Group. Transplantation 67:1036, 1999 9. Vincenti F, Ramos E, Brattstrom C, et al: Multicenter trial exploring calcineurin inhibitors avoidance in renal transplantation. Transplantation 71:1282, 2001 10. Johnson RW, Kreis H, Oberbauer R, et al: Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 72:777, 2001 11. Gonwa TA, Hricik DE, Brinker K, et al: Sirolimus Renal Function Study Group. Improved renal function in sirolimustreated renal transplant patients after early cyclosporine elimination. Transplantation 74:1560, 2002 12. Neuberger J: Renal failure late after liver transplantation. Liver Transplan 8:922, 2002 13. Cohen AJ, Stegall MD, Rosen CB, et al: Chronic renal dysfunction late after liver transplantation. Liver Transplant 8:916, 2002 14. Gonwa TA, Klintmalm GB, Levy M, et al: Impact of pretransplant renal function on survival after liver transplantation. Transplantation 59:361, 1995 15. Gonwa TA, Mai ML, Melton LB, et al: Renal replacement therapy and orthotopic liver transplantation: the role of continuous veno-venous hemodialysis. Transplantation 71:1424, 2001 16. Gonwa TA, Mai ML, Melton LB, et al: End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment. Transplantation 72:1934, 2001 17. Trotter JF, Wachs M, Bak T, et al: Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). Liver Transplant 7:343, 2001 18. Chang GJ, Mahanty HD, Quan D, et al: Experience with the use of sirolimus in liver transplantation: use in patients for whom calcineurin inhibitors are contraindicated. Liver Transplant 6:734, 2000 19. Watson CJ, Friend PJ, Jamieson NV, et al: Sirolimus: a potent new immunosuppressant for liver transplantation. Transplantation 67:505, 1999 20. Zhu J, Wu J, Frizell E, et al: Rapamycin inhibits hepatic stellate cell proliferation in vitro and limits fibrogenesis in an in vivo model of liver fibrosis. Gastroenterology 117:1198, 1999 21. Jain A, Reyes J, Kashyap R, et al: Long-term survival after liver transplantation in 4,000 consecutive patients at a single center. Ann Surg 232:490, 2000 22. Fisher NC, Nightingale PG, Gunson BK, et al: Chronic renal failure following liver transplantation: a retrospective analysis. Transplantation 66:59, 1998 23. Lynn M, Abreo K, Zibari G, et al: End-stage renal disease in liver transplants. Clin Transplant 15(suppl 6):66, 2001 24. Porayko MK, Gonwa TA, Klintmalm GB, et al: Comparing nephrotoxicity of FK 506 and cyclosporine regimens after liver

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transplantation: preliminary results from US multicenter trial. US Multicenter Liver Study Group. Transplant Proc 27:1114, 1995 25. Dharnidharka VR, Kwon C, Stevens G: Serum cystatin C is superior to serum creatinine as a marker of kidney function: a meta-analysis. Am J Kidney Dis 40:221, 2002 26. Shimizu-Tokiwa A, Kobata M, Io H, et al: Serum cystatin C is a more sensitive marker of glomerular function than serum creatinine. Nephron 92:224, 2002

27. Schuck O, Gottfriedova H, Maly J, et al: Glomerular filtration rate assessment in individuals after orthotopic liver transplantation based on serum cystatin C levels. Liver Transplant 8:594, 2002 28. Tan GD, Lewis AV, James TJ, et al: Clinical usefulness of cystatin C for the estimation of glomerular filtration rate in type 1 diabetes: reproducibility and accuracy compared with standard measures and iohexol clearance. Diabetes Care 25:2004, 2002