SUPPLEMENTARY INFORMATION

Appendix 1: Search Strategy executed 1/29/09, updated 12/25/2009

A.  PUBMED  Retrieved Articles: 412
(("Sirolimus"[Mesh] OR "mTOR protein "[Substance Name] OR "rapamycin"[All Fields]) OR "rapamune"[All Fields]) AND ("Liver Transplantation"[Mesh] OR "hepatic transplantation"[All Fields] OR "liver"[All Fields] OR "olt"[All Fields] OR "ltx"[All Fields]) AND "humans"[MeSH Terms]

B.  EMBASE Retrieved Articles: 1006
1	exp rapamycin/ or exp rapamycin derivative/ or exp "Mammalian Target of Rapamycin Inhibitor"/ or rapamune.mp. or sirolimus.mp. or rapamycin.mp.	18046 	
2	exp liver transplantation/ or exp liver graft/ or hepatic transp*.mp. or liver transp*.mp. or liver graft.mp. or olt.mp. or ltx.mp. or liver.mp.	401135 	
3	exp liver transplantation/ or exp liver graft/ or hepatic transp*.mp. or liver transp*.mp. or liver graft.mp. or olt.mp. or ltx.mp. or exp Liver/	144577 	
4	3 and 2	141009 	
5	1 and 3	1180 	
6	limit 5 to human	1006 	

C.  CENTRAL Retrieved Articles: 16
1	exp rapamycin/ or exp rapamycin derivative/ or exp "Mammalian Target of Rapamycin Inhibitor"/ or rapamune.mp. or sirolimus.mp. or rapamycin.mp.	708 	
2	exp liver transplantation/ or exp liver graft/ or hepatic transp*.mp. or liver transp*.mp. or liver graft.mp. or olt.mp. or ltx.mp. or liver.mp.	11636 	
3	exp liver transplantation/ or exp liver graft/ or hepatic transp*.mp. or liver transp*.mp. or liver graft.mp. or olt.mp. or ltx.mp. or exp Liver/	3134 	
4	3 and 2	3125 	
5	1 and 3	16 	
6	limit 5 to human 	16 	

D.  COCHRANE Systematic review Retrieved Articles:4
1	exp rapamycin/ or exp rapamycin derivative/ or exp "Mammalian Target of Rapamycin Inhibitor"/ or rapamune.mp. or sirolimus.mp. or rapamycin.mp.	17 	
2	exp liver transplantation/ or exp liver graft/ or hepatic transp*.mp. or liver transp*.mp. or liver graft.mp. or olt.mp. or ltx.mp. or liver.mp.	699 	
3	exp liver transplantation/ or exp liver graft/ or hepatic transp*.mp. or liver transp*.mp. or liver graft.mp. or olt.mp. or ltx.mp. or exp Liver/	94 	
4	3 and 2	94 	
5	1 and 3	4 	
6	limit 5 to human 	4 	

E.  SCOPUS Retrieved Articles: 631
 (TITLE-ABS-KEY((("Liver Transplantation" OR "liver" OR ("liver" AND "transp*") OR ("hepatic" AND "transp*") OR "liver graft" OR "hepatic graft" OR "olt" OR "ltx") AND (sirolimus OR rapamycin OR rapamune OR mtor protein))) AND TITLE-ABS-KEY(clinical OR patient* OR recipient* OR followup OR human OR men OR women))

F.  WEB OF SCIENCE Retrieved Articles: 168
Topic=("Liver Transplantation" OR "liver" OR ("liver" AND "transp*") OR ("hepatic" AND "transp*") OR "liver graft" OR "hepatic graft" OR "olt" OR "ltx") AND Topic=(sirolimus OR rapamycin OR rapamune OR mtor protein) AND Topic=(clinical OR patient* OR recipient* OR followup OR human OR men OR women)
Timespan=All Years. Databases=SCI-EXPANDED. 
Refined by: Document Type=( PROCEEDINGS PAPER OR REVIEW ) 

Less Duplicates:   543

Full text and abstracts: 1694

Search Updated December 25 2009: 4 studies obtained for full text review 

A hand search of relevant journals and annual meetings was conducted. (Liver Transplantation, Hepatology, Gastroenterology, Annals of Hepatology, and American Journal of Transplantation).  To minimize publication bias, abstracts presented at annual meetings of the European Association for the Study of the Liver, Digestive Diseases Week, American Association for the Study of Liver Diseases, American Transplant Congress, and International Liver Transplantation Society from January 2000 to December 2009 were retrieved.

Appendix 2: List of excluded studies and primary reason for exclusion.  
Please note that a study could have been excluded for multiple reasons.

A.  DID NOT MEET INCLUSION CRITERIA

Study design: Randomized clinical trials or observational cohort studies
Participants 
a.	Primarily adult Liver transplant recipients 
b.	Presence of impaired renal function (creatinine ≥1.5mg/dL, on renal replacement therapy, glomerular filtration rate<60ml/min/1.73m2 or equivalent)

1.	Perkins JD. Old foe learns new ticks. Liver Transplantation 2006;12:683.

2.	Kneteman NM, Oberholzer J, Al Saghier M, Meeberg GA, Blitz M, Ma MM, Wong WW, et al. Sirolimus-based immunosuppression for liver transplantation in the presence of extended criteria for hepatocellular carcinoma. Liver Transpl 2004;10:1301-1311.

3.	Stelzmueller I, Biebl M, Graziadei I, Wiesmayr S, Margreiter S, Bonatti H. Regarding diarrhea in liver transplant recipients: Etiology and management. Liver Transplantation 2006;12:163-164.

4.	Nocera A, Andorno E, Tagliamacco A, Morelli N, Bottino G, Ravazzoni F, Casaccia M, et al. Sirolimus therapy in liver transplant patients: an initial experience at a single center. Transplant Proc 2008;40:1950-1952.

5.	Kornberg A, Kupper B, Tannapfel A, Thrum K, Wilberg J, Barthel E, Settmacher U. Adjuvant conversion to sirolimus in liver transplant patients with recurrent hepatocellular carcinoma - preliminary results. Transpl Int 2008;21:96-99.

6.	Watson CJE, Friend PJ, Jamieson NV, Frick TW, Alexander G, Gimson AE, Calne R. Sirolimus: A potent new immunosuppressant for liver transplantation. Transplantation 1999;67:505-509.

7.	McAlister VC, Gao Z, Peltekian K, Domingues J, Mahalati K, MacDonald AS. Sirolimus-tacrolimus combination immunosuppression. Lancet 2000;355:376-377.

8.	Trotter JF, Wachs ME, Trouillot TE, Bak T, Kugelmas M, Kam I, Everson G. Dyslipidemia during sirolimus therapy in liver transplant recipients occurs with concomitant cyclosporine but not tacrolimus. Liver Transpl 2001;7:401-408.

9.	Trotter JF, Wachs M, Bak T, Trouillot T, Stolpman N, Everson GT, Kam I. Liver transplantation using sirolimus and minimal corticosteroids (3-day taper). In; 2001; 2001. p. 343-351.

10.	Nishida S, Pinna A, Verzaro R, Levi D, Kato T, Khan F, Nery J, et al. Sirolimus (rapamycin)-based rescue treatment following chronic rejection after liver transplantation. Transplant Proc 2001;33:1495.

11.	Vasquez EM. Sirolimus: a new agent for prevention of renal allograft rejection. Am J Health Syst Pharm 2000;57:437-448; quiz 449-451.

12.	Zimmerman MA, Trotter JF, Wachs M, Bak T, Campsen J, Skibba A, Kam I. Sirolimus-based immunosuppression following liver transplantation for hepatocellular carcinoma. Liver Transpl 2008;14:633-638.  Note:  Patients converted to sirolimus due to calcineurin inhibitor toxicity were excluded.  

13.	Campbell MS, Rai J, Kozin E, Bloom RD, Markmann JF, Olthoff KM, Shaked A, et al. Effects of sirolimus vs. calcineurin inhibitors on renal dysfunction after orthotopic liver transplantation. Clinical Transplantation 2007;21:377-384.  Note:  Patients who developed renal dysfunction prior to conversion were excluded.

14.	Maheshwari A, Torbenson MS, Thuluvath PJ. Sirolimus monotherapy versus sirolimus in combination with steroids and/or MMF for immunosuppression after liver transplantation. Dig Dis Sci 2006;51:1677-1684.

Interventions
c.	Sirolimus based immunosuppression
i.	Conversion from calcineurin inhibitor based therapy (tacrolimus or cyclosporine) OR
ii.	Sirolimus instituted for primary immunosuppression

De Boccardo G, Kim JY, Schiano TD, Maurette R, Gagliardi R, Murphy B, Emre S, et al. The Burden of Chronic Kidney Disease in Long-Term Liver Transplant Recipients. Transplantation Proceedings 2008;40:1498-1503.

Comparison interventions: 
d.	Presence of comparison group 
e.	Sirolimus vs. placebo OR
f.	Sirolimus versus calcineurin inhibitor based therapy (low dose or normal dose) OR 
g.	Sirolimus versus calcineurin inhibitor and mycophenolate mofetil OR
h.	Any combination therapy with sirolimus (with mycophenolate mofetil or IL2 receptor antibodies) vs. therapy without sirolimus 
i.	All doses of steroid (low dose, rapid taper, no steroid) or other secondary immunosuppression (eg. Azathioprine) eligible 

1.	Dehghani SM, Derakhshan A, Taghavi SAR, Gholami S, Jalaeian H, Malek-Hosseini SA. Prevalence and risk factors of renal dysfunction after liver transplant: A single-center experience. Experimental and Clinical Transplantation 2008;6:25-29.

2.	Montalbano M, Neff GW, Yamashiki N, Meyer D, Bettiol M, Slapak-Green G, Ruiz P, et al. A retrospective review of liver transplant patients treated with sirolimus from a single center: an analysis of sirolimus-related complications. Transplantation 2004;78:264-268.

3.	Peltekian K, McAlister VC, Colohan S, Gao Z, Salazar AB, Bitter-Suermann H, MacDonald AS. De novo use of low-dose tacrolimus and sirolimus in liver transplantation. Transplant Proc 2001;33:1341.

4.	Heffron TG, Smallwood GA, Davis L, Martinez E, Stieber AC. Sirolimus-based immunosuppressive [correction of immunosuppresive] protocol for calcineurin sparing in liver transplantation. Transplant Proc 2002;34:1522-1523.

5.	Pridohl O, Heinemann K, Hartwig T, Witzigmann H, Lamesch P, Fangmann J, Berr F, et al. Low-dose immunosuppression with FK 506 and sirolimus after liver transplantation: 1-year results. Transplant Proc 2001;33:3229-3231.

6.	Lam P, Yoshida A, Brown K, Abouljoud M, Bajjoka I, Dagher F, Moonka DK. The efficacy and limitations of sirolimus conversion in liver transplant patients who develop renal dysfunction on calcineurin inhibitors. Dig Dis Sci 2004;49:1029-1035.

7.	Perdigoto R, Sequeira C, Tome L, Ferrao J, Silva N, Geraldes J, Furtado E, et al. Sirolimus: efficacy in liver transplant patients with nephrotoxicity and renal insufficiency. Transplant Proc 2007;39:2519-2521.

8.	Yu S, He X, Yang L, Ma Y, Zhu X, Ju W, Huang J. A retrospective study of conversion from tacrolimus-based to sirolimus-based immunosuppression in orthotopic liver transplant recipients. Exp Clin Transplant 2008;6:113-117.

9.	Yang YJ, Chen DZ, Li LX, Kou JT, Lang R, Jin ZK, Han DD, et al. Sirolimus-based immunosuppressive therapy in liver transplant recipient with tacrolimus-related chronic renal insufficiency. Transplant Proc 2008;40:1541-1544.

10.	Yang YJ, Li LX, He Q, Fan H, Jin ZK, Lang R, Kou JT, et al. Sirolimus as primary immunosuppressant for calcineurin inhibitor-related renal insufficiency after liver transplantation. Hepatobiliary Pancreat Dis Int 2007;6:376-378.

11.	Morard I, Dumortier J, Spahr L, Hadengue A, Majno P, Morel P, Mentha G, et al. Conversion to sirolimus-based immunosuppression in maintenance liver transplantation patients. Liver Transpl 2007;13:658-664.

12.	Fisher A, Seguel JM, de la Torre AN, Wilson D, Merchant A, Arora RK, Koneru B. Effect of sirolimus on infection incidence in liver transplant recipients. Liver Transpl 2004;10:193-198.

13.	Wramner L, Norden G, Herlenius G, Friman S, Olausson M, Backman L. Conversion to sirolimus after kidney and liver transplantation: indications and outcomes. Transplant Proc 2003;35:791.

14.	Maheshwari A, Torbenson MS, Thuluvath PJ. Sirolimus monotherapy versus sirolimus in combination with steroids and/or MMF for immunosuppression after liver transplantation. Dig Dis Sci 2006;51:1677-1684.

15.	Sanchez EQ, Martin AP, Ikegami T, Uemura T, Narasimhan G, Goldstein RM, Levy MF, et al. Sirolimus conversion after liver transplantation: Improvement in measured glomerular filtration rate after 2 years. Transplantation Proceedings 2005;37:4416-4423.

16.	Kniepeiss D, Iberer F, Grasser B, Schaffellner S, Tscheliessnigg KH. Sirolimus in patients after liver transplantation. Transplant Proc 2003;35:815-816.

Primary Outcome of interest: 
j.	Renal function
i.	At prespecified interval: 1 month, 3 months, 6 months, 1 year, end of follow up 
ii.	Change in renal function
iii.	 Method of calculation:  GFR calculated by MDRD, or measured by cystatin C or iothalamate clearance, creatinine clearance, creatinine, change in GFR over interval, progression to renal replacement therapy or equivalent measures

1.	Willcocks LC, Chaudhry AN, Smith JC, Ojha S, Doffinger R, Watson CJ, Smith KG. The effect of sirolimus therapy on vaccine responses in transplant recipients. Am J Transplant 2007;7:2006-2011.

2.	Dunkelberg JC, Trotter JF, Wachs M, Bak T, Kugelmas M, Steinberg T, Everson GT, et al. Sirolimus as primary immunosuppression in liver transplantation is not associated with hepatic artery or wound complications. Liver Transpl 2003;9:463-468.

3.	Kniepeiss D, Iberer F, Schaffellner S, Jakoby E, Duller D, Tscheliessnigg K. Dyslipidemia during sirolimus therapy in patients after liver transplantation. Clin Transplant 2004;18:642-646.

B.	MET EXCLUSION CRITERIA

Other criteria: case control trials
Case reports, editorials, reviews and Letters that do not report original work, nonhuman trials

1.	Sindhi R. HSV infection and immunosuppression [1]. Liver Transplantation 2006;12:1906-1907.

2.	Broering DC, Walter J, Braun F, Rogiers X. Current Status of Hepatic Transplantation. Current Problems in Surgery 2008;45:587-661.

3.	Garcia M, Barcena R. Hepatocellular carcinoma and liver transplantation. [Spanish, English]. Revista Espanola de Enfermedades Digestivas 2006;98:891-898.

4.	Pengel L, Barcena L, Morris PJ. Registry of randomized controlled trials in transplantation. Transplantation 2005;80:432-440.
5.	Kakinoki K, Kaneko S. Management of the liver transplant recipients in the stable-phase. [Japanese]. Acta Hepatologica Japonica 2008;49:339-351.

6.	Kasner SE, Sheth KN, Wu GF, Messe SR, Wolf RL. Sirolimus may not cause neurotoxicity in kidney and liver transplant recipients. Neurology 2005;65:337-338; author reply 337-338.

7.	Lennon A, Finan K, FitzGerald MX, McCormick PA. Interstitial pneumonitis associated with sirolimus (rapamycin) therapy after liver transplantation. Transplantation 2001;72:1166-1167.

8.	Burroughs AK. Induction immunosuppression for patients who underwent transplantation for cirrhosis caused by hepatitis C? The answer is no! Liver Transplantation 2002;8:S47-S49.

9.	Izzedine H, Brocheriou I, Frances C. Post-transplantation proteinuria and sirolimus. N Engl J Med 2005;353:2088-2089.

10.	Fung J, Marcos A. Rapamycin: friend, foe, or misunderstood? Liver Transpl 2003;9:469-472.

11.	Rizell M, Cahlin C, Friman S, Hafstrom L, Lonn L, Olausson M, Lindner P. Impressive regression of primary liver cancer after treatment with sirolimus. Acta Oncol 2005;44:496.

12.	Post DJ, Douglas DD, Mulligan DC. Immunosuppression in liver transplantation. Liver Transplantation 2005;11:1307-1314.

13.	Gordon FD, Simpson M. Use of immunomodulary agents is difficult in treating autoimmune hepatitis patients. Journal of Clinical Gastroenterology 2004;38:729-730.

14.	Yoshida EM. Post-liver transplantation immunosuppression: the song does not remain the same. Can J Gastroenterol 2002;16:65-66.

15.	Te HS, Anderson AS, Millis JM, Jeevanandam V, Jensen DM. Current State of Combined Heart-Liver Transplantation in the United States. Journal of Heart and Lung Transplantation 2008;27:753-759.

16.	Kleuser B. Organ donation: Individual immunosuppression after transplantation. [German]. Pharmazeutische Zeitung 2008;153:16-25.

17.	Jensen GS, Wiseman A, Trotter JF. Sirolimus conversion for renal preservation in liver transplantation: not so fast. Liver Transpl 2008;14:601-603.

18.	Kibble A, Shumoogam J. American Society of Clinical Oncology - 43rd annual meeting. Translating research into practice. IDrugs 2007;10:509-512.

19.	Kaiser V, Klein A, Kramer I. Pharmaceutical care for patients with liver transplants. [German]. Pharmazeutische Zeitung 2007;152:64-71.

20.	Hepatocellular carcinoma after liver transplantation: Is it possible to lower the recurrence rate?. [German]. Klinikarzt 2005;34:XIV.

21.	Price N, Reddy GK. 46th Annual Meeting of the American Society of Hematology December 2004 San Diego, California. Clinical Lymphoma 2004;5:144-148.

22.	Morris PJ. 22nd Annual meeting of the International Society of Blood Purification (ISBP): Keynote Lecture and Abstracts. Blood Purification 2004;22:377-380.

23.	Beckebaum S, Cicinnati V, Brokalaki E, Frilling A, Gerken G, Broelsch CE. CNI-sparing regimens within the liver transplant setting: experiences of a single center. Clin Transpl 2004:215-220.

C.  DUPLICATE STUDIES
1.	Kniepeiss D, Iberer F, Schaffellner S, Jakoby E, Duller D, Tscheliessnigg K. Dyslipidemia during sirolimus therapy in patients after liver transplantation. Clin Transplant 2004;18:642-646.

2.	Willcocks LC, Chaudhry AN, Smith JC, Ojha S, Doffinger R, Watson CJ, Smith KG. The effect of sirolimus therapy on vaccine responses in transplant recipients. Am J Transplant 2007;7:2006-2011.

D.  INFORMATION ONLY AVAILABLE AT NATIONAL LIBRARY OF MEDICINE
Wang X, Wu YM, Xu ZC, Zhang B, Li ZC, Lu L, Zheng YS. Application of rapamycin in liver transplant patients with acute kidney malfunction. [Chinese]. World Chinese Journal of Digestology 2006;14:2974-2976.

E.  INFORMATION NOT AVAILABLE DESPITE AUTHOR CONTACT
1.  Wyeth Pharmaceuticals
Clinicaltrials.gov identifier: NCT00086346  
A Randomized, Open-Label, Comparative Evaluation of Conversion From Calcineurin Inhibitor Treatment to Sirolimus Treatment Versus Continued Calcineurin Inhibitor Treatment in Liver Allograft Recipients Undergoing Maintenance Therapy

2.  Spare the Nephron Trial, Hoffman La Roche Pharmaceuticals
Clinicaltrials.gov identifier: NCT00118742
A Randomized, Open-Label Study of the Effect of a Long-Term Calcineurin Inhibitor-Free Maintenance Regimen With CellCept and Sirolimus on Preservation of Renal Function and Prevention of Acute Rejection in Recipients of an Orthotropic Liver Transplant

F.  Updated search through December 25 2009.

1.	Di Benedetto F, Di Sandro S, De Ruvo N, Spaggiari M, Montalti R, Ballarin R, Cappelli G, et al. Sirolimus monotherapy effectiveness in liver transplant recipients with renal dysfunction due to calcineurin inhibitors. J Clin Gastroenterol 2009;43:280-286.
No comparison group

2.	Molinari M, Berman K, Meeberg G, Shapiro JA, Bigam D, Trotter JF, Kneteman N. Multicentric outcome analysis of sirolimus-based immunosuppression in 252 liver transplant recipients. Transpl Int 2009.
No extractable information on subset of patients with creatinine>1.5mg/dL.  The authors mention that the percent of patients with creatinine >2mg/dL decreased from 9.8% to 7% in the sirolimus arm and from 6.2% to 5.4% in the CNI arm.

3.	Yu S, He X, Yang L, Ma Y, Zhu X, Ju W, Huang J. A retrospective study of conversion from tacrolimus-based to sirolimus-based immunosuppression in orthotopic liver transplant recipients. Exp Clin Transplant 2008;6:113-117.
Normal renal function in comparison group.

4.	Zhou J, Wang Z, Wu ZQ, Qiu SJ, Yu Y, Huang XW, Tang ZY, et al. Sirolimus-based immunosuppression therapy in liver transplantation for patients with hepatocellular carcinoma exceeding the Milan criteria. Transplant Proc 2008;40:3548-3553.
     Renal outcomes not provided

Appendix 3: Details of imputation methods.  

The following imputations were made to obtain standard deviations.  For conversion from standard error (SE) to standard deviation (SD), we used the formula
Standard deviation= standard error/ sqrt (number of patients in group).  
If 95 % confidence interval was provided, we used the following relation to derive standard deviation:
½(width of 95% CI) = t x SD/sqrt (n), where the t statistic was derived from the p value associated with the change in renal function and the degrees of freedom (n-1).
In the event that additional information was not forthcoming, imputation of standard deviations was conducted using the following technique of imputation (14):
Sqrt [(SEbase)2 + (SEend)2 -2 (r) (SEbase) (SEend)] 
The correlation coefficient (r) describes within patient similarity at baseline and at the end of 12 months.  We calculated the correlation coefficient (r=0.57) using randomized controlled trials that provided the most complete information.(25)  To ensure that our assumptions did not change our conclusion, we considered a range of correlation coefficients (0.3-0.9).  The overall conclusions remained the same.  

Appendix 4: Details of included trials and observational studies.  

Study 	Shenoy 2007	
Study Design/Source of Information	Randomized Controlled Trial/Published data and author contacted-provided further information	
Patient	Inclusion: 6 months after liver transplantation, stable liver and renal function, creatinine clearance 40-80ml/min
Exclusion: Pre transplantation renal dysfunction, unstable liver function, pregnancy, myelosuppression, severe dyslipidemia, active infection	
Intervention	Sirolimus	
Control	Calcineurin Inhibitor (CNI) - cyclosporine or tacrolimus	
Outcome	Primary: Creatinine clearance 12 months after conversion (24 hour creatinine clearance)
Secondary: rejection and toxicity	
Notes	Follow up: 1 year (duration of trial)	

Study 	Watson 2007	
Study Design/Source of Information	Randomized Controlled Trial/Published data and author contacted-provided further information	
Patient	Inclusion: glomerular filtration rate (GFR) <65ml/min
Exclusion:  Acute rejection within the last 3 months, on hemodialysis, liver function tests> 2 x upper limit of normal, allergy to macrolide antibiotics, subnormal leukocyte or platelet counts, uncontrolled hypertension or hyperuricemia, pregnancy, hepatitis C patients enrolled in competing trial	
Intervention	Sirolimus	
Control	CNI - cyclosporine or tacrolimus	
Outcome	Primary: GFR at 12 months (Radioisotope labeled 51Cr-ethylenediaminetetraacetic acid-GFR)
Secondary: Graft and patient survival, dialysis requirement, treatment for hypertension, number of acute rejections, incidence of hypercholesterolemia, change in serum creatinine and uric acid, change in blood pressure, quality of life (SF-36)	
Notes	Follow up: 1 year (duration of trial)	

Study 	Eisenberger 2009	
Study Design/Source of Information	Randomized Controlled Trial/ Published data and author contacted-provided further information	
Patient	Inclusion: Creatinine clearance 40-90ml/min (Cockcroft-Gault), stable graft function
Exclusion:  Creatinine increase>30% during previous 8 weeks, switch to CNI within last 4 weeks, renal artery stenosis>50% reduction of luminal diameter, hydronephrosis grade II or worse, compression of kidney by adjacent masses	
Intervention	Sirolimus	
Control	CNI- cyclosporine or tacrolimus	
Outcome	Renal Resistive Indices, arterial stiffness, arterial blood pressure, graft rejection, renal function parameters (creatinine, proteinuria, GFR by 24 hour creatinine clearance, serum urea concentration).	
Notes	Follow up: 1 year, lack of data regarding randomization	

Study 	Montalbano 2004	
Study Design/Source of Information	Observational/ author contacted	
Patient	Acute Renal Failure at time of LTx: (1) hepatorenal syndrome (2) Cr>1.5	
Intervention	Sirolimus + Tacrolimus + Steroids (one received Daclizumab)`	
Control	Tacrolimus in all?	
Outcome	CrCl at 30, 60, and 90 days,1, 2, and 3 years, Sirolimus Toxicity/Tolerability, Graft Survival, Acute Cellular Rejection, Wound Closure, Death
	
Notes	Sirolimus started within 1 week of LTx, Follow-up: longest was 3 years	

Study 	Kneipeiss 2005	
Study Design/Source of Information	Observational/ author contacted but no reply obtained	
Patient	59 months (1-126) Post-LTx Renal insufficiency or Neurologic impairment, 	
Intervention	Sirolimus + MMF(all except 2 pt), 14 received Tacrolimus, 1 pt administered cyclosporine + Sirolimus, 1 pt received Sirolimus monotherapy	
Control	CNI (29 patients received CNI + MMF)	
Outcome	% of patients with mild/moderate/severe renal insufficiency in sirolimus vs. reference group at undefined interval follow-up (mean 12 months(2-26))	
Notes	Poorly defined inclusion/exclusion criteria; no pre-defined end-points; no predefined follow-up interval for analyzing endpoint	

Study 	Smallwood 2005	
Study Design/Source of Information	Observational/ author contacted but no further information obtained
Abstract information only	
Patient	Creatinine>1.7mg/dL	
Intervention	Sirolimus 	
Control	Mycophenolate Mofetil	
Outcome	Creatinine at 12 months, 1,2,3,4 years, progression to hemodialysis, acute rejection, death, infections	
Notes	No CNI arm; abstract data only-combined data from 2 abstracts	

Study 	Zaghla 2006	
Study Design/Source of Information	Observational/author contacted but no reply obtained	
Patient	Inclusion: Primary Initial Immunosuppression with Sirolimus
Exclusion: Sirolimus was not the initial immunosuppressant – started > 2 weeks after LTx; Sirolimus discontinued within 3 months of LTx	
Intervention	(SA) – Sirolimus Alone +/- mycophenolate mofetil (MMF); (SC) – Sirolimus w/ CNI +/- MMF	
Control	(CNI) CNI without Sirolimus +/- MMF	
Outcome	Graft and Patient survival, incidence of ACR at 1,3,6, 12 months after transplantation, renal function, need for dialysis, hematologic parameters, incidence of vascular, biliary, and wound healing complications, 	
Notes	Percentage of patients with hepatorenal syndrome (HRS) in each group is unknown; HRS would be reversible with LTx and a disproportionate percent of HRS in one group vs. another could skew outcomes	

Study 	Dubay 2008	
Study Design/Source of Information	Observational Study/author contacted but further information not provided	
Patient	Inclusion: Renal Failure (CrCl<60ml/min), post-LT, Sirolimus
Exclusion: <90 days post-LTx	
Intervention	Sirolimus monotherapy or sirolimus +/-antimetabolite +/- steroids (5 patients remained on low dose CNI)	
Control	Low dose calcineurin inhibitor: median levels for cyclosporine was 400 μg/L (range 100-700 μg/L), whereas the median serum trough tacrolimus levels were 6 μg/L (range 2.5-10.5 μg/L).	
Outcome	Renal function (3,6, and 12 months), renal replacement therapy, sirolimus toxicity, Acute cellular rejection, re-transplantation, death	
Notes	Follow up: 1 year
10 patients had no suitable controls; 10 patients who started sirolimus in the early postoperative period (less than 90 days) were excluded; One other patient who was treated with sirolimus for less than 90 days was also excluded.	

Study 	Thompson 2008	
Study Design/Source of Information	Observational/ author contacted but no further information obtained
Abstract information only	
Patient	Creatinine>2	
Intervention	Sirolimus	
Control	MMF + Prednisone	
Outcome	Most recent creatinine	
Notes	No CNI arm; abstract data only; Mean f/u 28.4 months; creatinine not provided at defined intervals, unsure of graft failure reporting	

Study 	Zhang 2008	
Study Design/Source of Information	Observational, translated	
Patient	Sparse details	
Intervention	Sirolimus + MMF + Prednisone	
Control	CYC/Tac at reduced doses - the target was lower limit of range : level of tacrolimus to 10-12ng/ml; cyclosporine to 250-300 ng/ml	
Outcome	Creatinine at 6 months	
Notes	control group was 18.3+/- 5.5 m and 14-34 m for study group; 12 month data not available; unsure of matching criteria	

Study 	Rogers 2009	
Study Design/Source of Information	Observational Study/ abstract and accepted manuscript copy obtained from author 	
Patient	Inclusion:  Serum creatinine >30% above baseline or GFR 30-55 ml/min OR hepatocellular carcinoma >6 weeks from transplant, CNI, neurological or gastrointestinal toxicity, normal hepatic vasculature by ultrasound
Exclusion: leukopenia, thrombocytopenia (75,000), severe dyslipidemia	
Intervention	Sirolimus	
Control	Calcineurin Inhibitor- cyclosporine or tacrolimus	
Outcome	Primary:  Change in renal function (serum creatinine and estimated GFR by the MDRD equation) from conversion to last follow up. Patients
Secondary: Rejection and adverse events	
Notes	Patients divided into early and late conversion (3 months).
Follow up:  1.2 (0.9) early conversion and  1.3 (0.2) years in late conversion group
74% of the patients received sirolimus due to renal insufficiency; authors contacted to provide further information regarding this subset not available, adverse events reported for entire group.
Only 42/72 patients converted to sirolimus had more than 3 months follow up data.
Inconsistent reporting of adverse events.	

Appendix 5: Standardized Mean Difference of change in renal function from initiation of sirolimus to 1 year including studies with incomplete data.  

Standardized Mean Difference of change in renal function from initiation of sirolimus to 1 year.  Test for subgroup interaction was not significant (p=0.82).  Inclusion of these borderline eligible observational studies yields a more favorable result, SMD 0.89 [95% CI 0.23 - 1.55] or an improvement of 10.03 ml/min (95% CI 3.27 to 17.47).  Imputations for standard deviation were required for all studies except for Watson et al. 2007 and Shenoy et al. 2007.  Smallwood et al. 2005, Kniepeiss et al. 2005 and Zaghla et al. 2006 only reported creatinine.  The mean values in studies reporting serum creatinine were multiplied by -1 to make the scale uniform.  Rogers et al. 2009 did not provide estimates of GFR at 1 year in the reference arm and only reported values prior to transplant and end of study (616 +/- 459 days).  Zhang et al. 2008 reported two separate sirolimus and reference groups by time of initiation (within 3 months or 3-9 months) and change at 6 months was provided. Kniepeiss et al. 2005 did not provide estimates of variability.   The mean change is reported but not included in the pooled estimate.  Montalbano et al. 2004 did not provide estimates of variability.  The mean change is reported but not included in the pooled estimate.  Not enough data available to include Thompson et al. 2008. 

Appendix 6: Pooled relative risk estimates 
for side effects and adverse events at 1 year

The individual trials providing information for each of the outcomes at 1 year are provided below.  Trials with no events in either arm have also been included by imputing 1 event in each arm.  A sensitivity analysis by excluding the trial or imputing 0.5 in each group did not change the results.

4.1 Death

•	Eisenberger 2009 had zero events in each arm and the relative risk after excluding this study is 1.12 [0.66, 1.91].
•	Shenoy 2007 had 2 total deaths in control arm but 1 of the deaths occurred after completion of the study. 
•	Smallwood 2005 reported the number of deaths within first 3 months. 

4.2 Graft Failure

•	Eisenberger 2009 had zero events in each arm and the relative risk after excluding this study is 0.79 [0.44, 1.42]

4.3 Acute Rejection

•	Eisenberger 2009 had zero events in each arm and the relative risk after excluding this study is 0.88 [0.43, 1.79]
•	Rogers 2009 and Thompson 2008 were excluded from the pooled estimate because the number of events limited to the first year is unknown.  If both these studies are included then the relative risk of acute rejection is 1.02 (95% CI 0.60-1.73) 

4.4 Renal replacement Therapy

•	Eisenberger 2009 and Watson 2007 had zero events in each arm and the relative risk after excluding these studies is 2.08 [0.94, 4.61]
•	Among the three controlled trials (n=86), there was only 1 incidence of requiring renal replacement therapy in the sirolimus arm. Therefore the increased relative risk of renal replacement therapy is limited to observational studies suggesting a selection bias.  
•	Shenoy 2007 had 2 patients requiring renal replacement therapy but 1 required it after completion of study. 
•	Zaghla 2006: 1 year data for renal replacement therapy is only available for 14/28 and 66/101 total patients.  Results do not change if all patients are included in the denominator (28 and 101).  
•	Smallwood 2005 was excluded from the pooled estimate because the number of events limited to the first year is unknown.  If this study is included then the relative risk of renal replacement therapy is 2.11 [1.11, 4.02]  

4.5 Infection

•	Rogers 2009 and Smallwood 2005 were excluded from the pooled estimate because the number of events limited to the first year is unknown.  If both these studies are included then the relative risk of infection is 1.95 [1.07, 3.53]

4.6 Statin Use

•	Rogers 2009 was excluded from the pooled estimate because the number of events limited to the first year is unknown.  If this study is included then the relative risk of de novo statin use is 1.92 [0.97, 3.79]

4.7 Rash

•	Rogers 2009 was excluded from the pooled estimate because the number of events limited to the first year is unknown.  If this study is included then the relative risk of rash is 3.48 [1.29, 9.36]
4.8 Ulcer

•	Rogers 2009 was excluded from the pooled estimate because the number of events limited to the first year is unknown.  If this study is included then the relative risk of oromucosal ulcers is 6.23 [2.35, 16.49]

4.9 Edema

•	Rogers 2009 was excluded from the pooled estimate because the number of events limited to the first year is unknown.  If this study is included then the relative risk of edema is 2.41 [1.11, 5.23]

4.10 Proteinuria

4.11 Poor wound healing

•	Shenoy 2007 had zero events in each arm and the relative risk after excluding this study is 1.76 [0.43, 7.26]
•	Rogers 2009 was excluded from the pooled estimate because the number of events limited to the first year is unknown.  If this study is included then the relative risk of edema is 0.74 [0.23, 2.35]

4.12 Discontinuation of medication

•	Does not include discontinuation for deaths
•	Does not include the following trials as events in the reference group were not reported.  Rates of discontinuation in the sirolimus arm were:
o	Dubay 2008: 		33% (19/57)
o	Montalbano 2004: 	33% (4/12)
o	Rogers 2009: 		55.5% (40/72)