12 and 5mg/kg every 4 weeks from month 3 versus CYA 4-10mg/kg daily, adjusted to trough level 150-300ng/ml through month 1 then 100-250ng/ml from month 2 Belatacept 10mg/kg IV day 1, 5, 15, 29, 43, 57, 71, 85, 113, 141, 169 and 5mg/kg every 4 or 8 weeks thereafter versus Belatacept 10mg/kg IV day 1, 15, 29, 57, 85 then 5mg/kg every 4 or 8 weeks thereafter versus CYA 4- 10mg/kg daily, adjusted to trough level 150-400ng/ml through month 1 then 100-300ng/ml from month 2

MMF 2g daily, corticosteroids

Acute rejection 128 60

Bortezomib versus placebo

Eskandary et al,⁵⁴2018 Kidney transplant with Kidney, kidney- Bortezomib IV 4 x 1.3mg/m²over 2 weeks and None Graft function 44 24 AbMR; 5 pancreas valacyclovir 500mg daily for 3 weeks versus placebo

CYA high dose versus CYA low dose

Dantal et al,⁴⁷1998 Kidney transplant with ≤1 Kidney CYA adjusted to trough level 150-250ng/ml versus CYA None Graft function 231 67 episode rejection in first adjusted to trough level 75-125ng/ml

year post transplant; not stated

CYA early versus CYA late

Mourad et al,⁸⁴2007 Kidney; 0 Kidney CYA initiated day 0 versus CYA initiated day 6, both EC-MPS 720mg Graft function 203 30 dosed 8mg/kg daily adjusted to 2-hr level 1300ng/ml twice daily,

week 0-6, then 1150ng/ml week 6-12, then 900ng/ml corticosteroids month 4-6, then 700ng/ml afterwards

TAC versus CYA

Gaber et al,⁵⁹2008 Kidney transplant with ≥1 Kidney TAC adjusted to trough level 10-15ng/ml week 1-2, then SRL adjusted to Composite first 448 12 high risk factor (black 5-10ng/ml week 2-26, then 3-5ng/ml week 26-52 versus trough level 10- acute rejection,

ethnicity, non primary CYA adjusted to whole blood level 200-300ng/ml in week 15ng/ml, graft loss, or

6 Change in 46

serum and urinary BK viral load

FK778 600mg loading dose then 100mg daily, adjusted CNI dose reduction to trough level 40-120µg/mL versus MMF dose reduction by 40-60%,

by 40-60% corticosteroids

maintained Kidney

Kidney transplant with BK nephropathy; not stated FK778 versus reduction in

immunosuppression Guasch et al,⁶⁵2010

(10)

renal transplant, or PRA 1-2, then 150-200ng/ml week 2-26, then 100-150ng/ml corticosteroids death

>80%); not stated week 26-52

Grimm et al,⁶³2006 Heart transplant; not Heart TAC adjusted to trough level 10-20ng/ml months 1-3, AZA 2-4mg/kg/day, Acute rejection 314 18 stated then 5-15ng/ml versus CYA adjusted to trough level 200- corticosteroids

350ng/ml months 1-3, then 100-200ng/ml

Guethoff et al,⁶⁶2013 Heart transplant; 0 Heart TAC adjusted to trough level 13-15ng/ml months 0-6, MPA adjusted to Patient survival 60 108 then 10-12ng/ml months 7-12, then 8-10ng/ml year 2, target level 2.5-

then 6-8ng/ml year 3-4, then 4-7ng/ml year 5-10 versus 4.0µg/ml month 0-6, CYA adjusted to target level 200-300ng/ml months 0-6, then 1.5-2.5µg/ml then 150-200ng/ml months 7-24, then 100-150ng/ml year month 7 to year 10;

3-10 corticosteroids

Kobashigawa et al,⁷⁵2006 Heart transplant; 0 Heart TAC 2-4mg daily adjusted to trough level 10-20ng/ml MMF 3g daily Acute rejection 343 12 months 1-3, then 5-15ng/ml afterwards versus CYA 3- adjusted to trough

5mg/kg daily adjusted to trough level 200-400ng/ml level 3-5ng/ml months 1-3, then 100-300ng/ml afterwards

Kuypers et al,⁷⁶2005 Kidney-pancreas Kidney- TAC 0.2mg/kg daily versus CYA 7mg/kg daily MMF, Graft survival 205 Not

transplant; not stated pancreas corticosteroids stated

Levy et al,⁸⁰2006 Liver transplant; 0 Liver TAC 0.1-0.15mg/kg daily adjusted to trough level 5- AZA, corticosteroids Graft survival, 495 12 15ng/ml month 1-3, then 5-12ng/ml to month 6, then 5- patient survival

10ng/ml afterwards versus CYA 10-15mg/kg daily adjust to a 2-hr level 800-1200ng/ml month 1-3, then 700- 900ng/ml to month 6, then 500-700ng/ml afterwards

Silva et al,⁹⁸2014 Kidney transplant; 0 Kidney TAC extended release or conventional release 0.15- MMF 1g twice daily, Composite graft 668 48 0.20mg/kg daily adjusted to trough level 7-16ng/ml for corticosteroids loss, acute

day 0-90 then 5-15ngml afterwards versus CYA 4- rejection, or lost 5mg/kg twice daily adjusted to trough level 125-400ng/ml to follow-up day 0-90 then 100-300ng/ml afterwards

CYA + MMF versus TAC high dose + SRL low dose versus TAC low dose + SRL high dose

Suszynski et al,¹⁰⁴2013 Kidney transplant; 0 Kidney CYA 8mg/kg daily adjusted to trough levels 150-200ng/ml month 1-3 + MMF 1g (non African American) or 1.5g (African American) twice daily versus TAC 0.03mg/kg twice daily adjusted to trough levels 8-12ng/ml + SRL

Corticosteroids Composite of graft loss, death or re-transplant for chronic

440 84

(11)

2mg daily adjusted to trough levels 3-7ng/ml versus TAC 0.015mg/kg twice daily adjusted to trough levels 3-7ng/ml + SRL 5mg daily adjusted to trough levels 8-12ng/ml

rejection

Alemtuzumab versus conventional induction therapy

Hanaway et al,⁶⁹2011 Kidney transplant; 0 Kidney Alemtuzumab IV 30mg at time of transplantation versus basiliximab IV 20mg x2 (low-risk patients) or rATG IV 1.5mg/kg x4

TAC, MMF, corticosteroids

Acute rejection 501 36

Basiliximab versus daclizumab

Kandus et al,⁷⁴2010 Kidney transplant with ≥1 Kidney Basiliximab IV 20mg day 0, 4 versus daclizumab IV CYA, MMF, Acute rejection 212 12

HLA mismatch; 0 1mg/kg day 0 and week 2, 4, 6, 8 corticosteroids

Anti-IL2 versus placebo or no treatment

Van Gelder et al,¹¹¹1995 Kidney transplant; 0 Kidney BT563 IV 10mg day 0-10 versus placebo CYA, Acute rejection 60 12 corticosteroids

Stratta et al,¹⁰³2005 Kidney-pancreas Kidney- Daclizumab IV 1mg/kg every 14 days for 5 doses versus TAC, MMF, Acute rejection, 298 36 transplant; 0 pancreas daclizumab 2mg/kg every 14 days for 2 doses versus no corticosteroids graft loss or

60 Anti-CD2 IV 10mg daily for 10 days versus no treatment TAC, corticosteroids Acute rejection 40

Liver Liver transplant; 0

Anti-CD2 versus no treatment

Lerut et al,⁷⁹2005

3 Proportion 240

achieving desired trough level on day 3 TAC 0.2mg/kg daily versus dosing by CYP3A5 genotype MMF 1g bd

(CYP3A5 expressers 0.30mg/kg daily, CYP3A5 non adjusted to trough expressers 0.15mg/kg daily) level 1.5-3.0mg/L,

corticosteroids Kidney

Kidney transplant from living donor; 0 TAC standard dosing

versus dosing by CYP3A5 genotype

Shuker et al,⁹⁶2016

(12)

treatment death Anti-CD40 versus standard

care

Harland et al,⁷⁰2015 Kidney transplant; not Kidney Anti-CD40 + TAC adjusted to trough level 4-11ng/ml day None Acute rejection 138 6

stated 0-30, then 2-5ng/ml afterwards or MMF 1g twice daily

versus TAC adjusted to trough level 4-11ng/ml day 0-30, then 2-5ng/ml afterwards + MMF 1g twice daily rATG single dose versus

rATG double dose

Stevens et al,¹⁰²2016 Kidney transplant; 0 Kidney rATG 6mg/kg versus rATG 1.5mg/kg x4 Methylprednisone, Composite of 97 12 diphenhydramine, fever,

paracetamol, TAC, hypotension, MMF or MPA hypoxia, cardiac

events, DGF rATG versus anti-IL2

Lentine et al,⁷⁸2015 Kidney transplant from Kidney rATG 1.5mg/kg day 0-4 versus basiliximab IV 20mg day CYA, MMF, Rejection, graft 183 120

deceased donor; 0 0, 4 corticosteroids survival, patient

survival

Mullen et al,⁸⁶2014 Heart transplant; 0 Heart rATG 10mg/kg infused continuously from day 0 until day CYA or TAC, MMF, Infection 30 12 5 to 7 versus daclizumab IV 2mg/kg day 0 then 1mg/kg corticosteroids

day 4 rATG versus no treatment

or placebo

Cantarovich et al,⁴¹2008 Kidney transplant from Kidney rATG + AZA 1mg/kg daily initiated day 45-90 versus AZA CYA, Acute rejection 123 240

deceased donor; 0 1.5mg/kg daily corticosteroids

Snell et al,¹⁰⁰2014 Lung transplant; 0 Lung rATG 5mg/kg versus rATG 9mg/kg versus placebo TAC/AZA or Composite graft 223 12 TAC/MMF or loss, death,

CYA/MMF, acute rejection, corticosteroids lost to follow-up Sphingosine 1-phosphate

receptor modulators versus MMF

(13)

Mulgaonkar et al,⁸⁵2006 Kidney transplant; 0 Kidney FTY720 5mg + reduced dose CYA versus FTY720 2.5mg Corticosteroids Composite 261 12 + reduced dose CYA versus FTY720 2.5mg + full dose acute rejection,

CYA versus MMF + full dose CYA graft loss, death

or premature study

discontinuation MMF versus AZA

Clayton et al,⁴⁵2012 Kidney transplant from Kidney MMF 1.5g twice daily versus MMF 1g twice daily versus CYA, Acute rejection, 503 165.5 deceased donor; 0 AZA 100mg (body weight <75kg) or 150mg (body weight corticosteroids graft loss,

≥75kg) daily death, drug

discontinuation

<6 months

Eisen et al,⁵³2005 Heart transplant; 0 Heart MMF 1.5g twice daily versus AZA 1.5-3mg/kg daily CYA, Composite 578 36 corticosteroids death or re-

transplant

Remuzzi et al,⁸⁹2007 Kidney transplant from Kidney MMF 1g twice daily versus AZA 100mg (body weight CYA, Graft function 334 64.8 deceased donor; 0 <75kg) or 150mg (body weight ≥75kg) daily corticosteroids

Thierry et al,¹⁰⁶2016 Kidney transplant from Kidney MMF 2g daily tapered by 500mg every 2-4 weeks to 1g CYA, Patient survival, 204 111.6 deceased donor; 1 daily versus AZA 1-2mg/kg daily versus no treatment corticosteroids graft survival

MMF versus EC-MPS

Budde et al,³⁸2005 Kidney transplant; 3 Kidney MMF 2g daily versus EC-MPS 1.44g daily CYA Composite of 287 12

acute rejection, graft loss, death

Salvadori et al,⁹¹2004 Kidney transplant; 0 Kidney MMF 1g twice daily versus EC-MPS 720mg twice daily CYA, Acute rejection, 423 12 corticosteroids graft loss,

death, loss to follow-up mTORi versus CNI

Alberú et al,³³2011 Kidney transplant; 3 Kidney SRL 4-8mg daily, adjusted to trough level 8-20ng/ml MMF or AZA, Malignancy, 824 24 versus CNI (CYA adjusted to trough level 50-250ng/ml or corticosteroids infection, non

TAC adjusted to trough level 4-10ng/ml) infection-related

adverse events

Campbell et al,³⁹2012 Kidney transplant with Kidney SRL 2-4mg daily, adjusted to trough level 5-15ng/ml MMF or AZA, Non melanoma 87 20

previous skin cancer versus CNI continuation corticosteroids skin cancer

(14)

within last 3 years; 9

Euvrard et al,⁵⁵2012 Kidney transplant with Kidney SRL adjusted to trough level 6-12ng/ml versus CNI (CYA None Skin cancer 120 24 previous skin cancer; 1 adjusted to trough level 75-125ng/ml or TAC adjusted to survival

trough level 4-7ng/ml)

Flechner et al,⁵⁷2007 Kidney transplant; 0 Kidney SRL 5mg daily, adjusted to trough level 10-12ng/ml MMF, Acute rejection, 61 60 month 1-6, then 5-10ng/ml afterwards versus CYA 6- corticosteroids graft function

8mg/kg daily, adjusted to trough level 200-250ng/ml

Flechner et al,⁵⁸2011 Kidney transplant; 0 Kidney SRL 5mg daily, adjusted to trough level 10-15ng/ml MMF Graft function 295 14 through week 13, then 8-15ng/ml through week 26, then

5-15ng/ml afterwards versus TAC 0.2mg/kg daily, adjusted to trough level 8-15ng/ml through week 26, then 5-15ng/ml afterwards

Gatault et al,⁶¹2016 Kidney transplant; 0 Kidney SRL 10mg daily, adjusted to trough levels 10-15ng/ml MMF, Graft function 145 96 versus CYA 6-8mg/kg daily, adjusted to trough levels corticosteroids

150-250ng/ml month 1-3, then 75-150ng/ml afterwards

Lebranchu et al,⁷⁷2009 Kidney transplant; 0.25 Kidney SRL 6mg daily, adjusted to trough levels 8-15ng/ml MMF, Graft function 193 12 through week 39, then 5-15ng/ml afterwards versus CYA corticosteroids

adjusted to a 2-hr level 500-800ng/ml

Mjornstedt et al,⁸³2012 Kidney transplant; 0 Kidney EVL adjusted to trough level 6-10ng/ml versus CYA EC-MPS, Graft function 204 12 adjusted to trough level 75-200ng/ml month 1-6, then 50- corticosteroids

150ng/ml afterwards

Sebbag et al,⁹⁴2016 Heart transplant; with Heart EVL 0.75mg/kg twice daily, adjusted to trough level 3- None Non melanoma 39 Not

previous keratotic skin 8ng/ml versus CNI skin cancer or stated

lesions or skin cancer; not new keratotic

stated skin lesions

Sommerer et al,¹⁰¹2016 Kidney transplant; 0.33 Kidney EVL adjusted to trough level 6-10ng/ml versus CYA EC-MPS, Graft function 300 60 adjusted to trough level 120-180ng/ml through month 6, corticosteroids

then 100-150ng/ml afterwards

Tedesco-Silva et al,105 Kidney transplant; not Kidney SRL adjusted to trough level 7-15ng/ml through month 12 MMF or MPS Graft function 254 24

2016 stated then 5-15ng/ml afterwards versus TAC dosed as per

investigator’s standard of care

Watson et al,¹¹⁵2007 Liver transplant with Liver SRL 2mg daily, adjusted to trough level 5-15ng/ml versus None Renal function 30 12 impaired renal function; 4 CNI (CYA or TAC)

Weir et al,¹¹⁶2017 Kidney transplant; not Kidney SRL 2mg daily, adjusted to trough level 5-10ng/ml versus MMF, Graft function 128 60

stated CNI (CYA or TAC) corticosteroids

Heart transplant with SRL 1-5mg daily, adjusted to trough level 7-15ng/ml

(15)

Zuckermann et al,¹²¹2012 impaired renal function; 4 Heart versus CNI dosed as per investigator’s standard of care None Renal function 116 12

mTORi + CNI low-dose versus CNI standard-dose

Andreassen et al,³⁴2016 Heart transplant; 0 Heart EVL 0.75mg bd, adjusted to trough level 3-6ng/ml week MMF, Graft function 115 36

Asrani et al,³⁵2014 Liver transplant; 0 Liver

1-7 then 6-10ng/ml afterwards, plus CYA adjusted to trough level 75-175ng/ml week 1-7 then ceased versus CYA adjusted to trough level 150-350ng/ml months 1-2, then 100-250ng/ml months 3-6, then 60-200ng/ml months 7-12

SRL 5mg daily, adjusted to trough level 4-11ng/ml, plus

corticosteroids

Corticosteroids Composite of 222 24 TAC 0.03-0.05mg daily, adjusted to trough level 3-7ng/ml

month 1-3, then 3-5ng/ml afterwards versus TAC 0.06- 0.10mg daily, adjusted to trough level 7-15ng/ml month 1-3, then 5-10ng/ml afterwards

acute rejection, graft loss, death

Gullestad et al,⁶⁷2016 Heart or lung transplant;

not stated

Heart, lung EVL 0.75-1.5mg twice daily, adjusted to trough level 3- 8ng/ml, plus CNI (CYA trough level <75ng/ml or TAC trough level <4ng/ml) versus CNI

None Graft function 163 64

mTORi versus other treatment

Chadban et al,⁴³2016 Kidney transplant; not Kidney EVL 1.5mg or 3.0mg versus CYA plus MPA None Non melanoma 95 84 Hoogendijk et al,⁷³2013

stated

Kidney transplant with Kidney SRL adjusted to trough level 5-10ng/ml versus original Corticosteroids

skin cancer

Non melanoma 155 24 Salgo et al,⁹⁰2010

previous skin cancer; 18

Kidney transplant with Kidney

immunosuppression regime

SRL adjusted to trough level 6-8ng/ml versus original None

skin cancer

Keratotic skin 44 12

Segovia et al,⁹⁵2012

previous keratotic skin lesion or skin cancer; 19

Heart transplant with Heart

immunosuppression regime

EVL with reduced dose CYA versus conventional None

lesion response

Adverse events 52 24

Sikora et al,⁹⁷2017

cardiac allograft vasculopathy; not stated

Lung transplant; not Lung

immunosuppression

EVL versus MMF CYA, Non melanoma 190 101

stated corticosteroids skin cancer

(16)

mTORi immediate versus mTORi delayed

Dantal et al,⁴⁶2010 Kidney transplant from deceased donor; 0

Kidney EVL commenced day 1 post transplantation at 0.75mg twice daily, adjusted to trough levels 3-8ng/ml versus MMF or EC-MPS commenced day 1 post transplantation replaced by EVL at week 5 at 0.75mg twice daily, adjusted to trough levels 3-8ng/ml

CYA,

corticosteroids

Composite of DGF, acute rejection, graft loss, death, wound healing complications, or lost to follow- up

139 12

mTORi standard dosing versus mTORi high dose

Salvadori et al,⁹²2009 Kidney transplant; 0 Kidney EVL 0.75mg twice daily, adjusted to trough level 3-8ng/ml plus CYA 2mg/kg twice daily, adjusted to 2-hr level 500- 700ng/ml through month 2, then 350-500ng/ml through month 6, then 350-450ng/ml afterwards versus EVL 0.75mg twice daily, adjusted to trough level 8-12ng/ml plus CYA 2mg/kg twice daily, adjusted to 2-hr level 500- 700ng/ml through week 1, then 250-450ng/ml through month 2, then 200-400ng/ml through month 4, then 150- 300ng/ml afterwards

Corticosteroids Graft function 285 12

mTORi + corticosteorids versus other treatment

Carroll et al,⁴²2013 Kidney transplant; with previous skin cancer; not stated

Kidney SRL adjusted to trough level 5-10ng/ml, plus prednisone 5mg daily versus original immunosuppression regime

None Non melanoma

skin cancer

32 24

Paricalcitol versus no treatment

Pihlstrom et al,⁸⁸2017 Kidney transplant; not stated

Kidney Paricalcitol 2µg daily versus no treatment None Albuminuria 77 10

Statin versus placebo

Holdaas et al,⁷²2005 Kidney transplant; 5 Kidney Fluvastatin 40mg daily, increased to twice daily at 2 years versus placebo

None Composite

cardiac death,

2102 60

(17)

cardiovascular events or interventions

CNI withdrawal versus CNI continuation

Abramowicz et al,³²2005 Kidney transplant; not Kidney CYA withdrawal over 12 weeks versus CYA continuation MMF, Acute rejection, 151 48

stated corticosteroids graft loss, death

Campistol et al,⁴⁰2006 Kidney transplant; 0.25 Kidney CYA withdrawal over 4-6 weeks versus CYA SRL, corticosteroids Graft survival, 430 60 continuation, adjusted to trough levels 75-200ng/ml patient survival

CNI conversion to MMF versus CNI continuation

Schmeding et al,⁹³2011 Liver transplant; 5 Liver CYA withdrawal over 12 weeks plus MMF introduction None Acute or chronic 142 60

over 4 weeks versus CYA continuation rejection

Corticosteroid withdrawal versus corticosteroid continuation

Cantarovich et al,³⁰2014 Kidney transplant from Kidney No corticosteroids from transplantation unless clinically MMF, CYA Time to acute 204 60 deceased donor; 0 indicated (eg. acute rejection) versus corticosteroids for rejection

at least 6 months, after which it could be discontinued or continued according to local practice

Vincenti et al,³¹2008 Kidney transplant; 0 Kidney No corticosteroids from transplantation versus EC-MPS, CYA Graft function 337 12 corticosteroids for 1 week then ceased versus oral

prednisone 60mg daily tapered to 20mg daily by day 7, then 10-30mg daily through month 1, then 10-20mg daily through month 2, then 5-10mg daily

Vitko et al,¹¹⁴2005 Kidney transplant; 0 Kidney No corticosteroids from transplantation plus basilixmab IV TAC Time to acute 457 6 20mg at day 0, 4 versus no corticosteroids plus MMF 2g rejection

daily through week 2 then 1g daily versus MMF 2g daily through week 2 then 1g daily plus corticosteroids

Woodle et al,¹¹⁸2008 Kidney transplant; 0 Kidney No corticosteroids from day 7 post transplantation versus TAC, MMF Composite of 397 60 oral prednisone 0.4mg/kg day 8-14, then 0.3mg/kg day death, graft

15-29, then 0.2mg/kg day 30-89, then 0.15mg/kg day 90- loss, moderate 119, then 0.1mg/kg day 120-180, then 5mg daily or severe acute

(18)

ATRA = all-trans retinoid acid; MAL= methyl aminolaevulinate; ACE = angiotensin converting enzyme; AZA = azathioprine; CYA = cyclosporin A; CNI = calcineurin inhibitor; TAC = tacrolimus; IV= intravenous; MMF = mycophenolate mofetil;

MPA = mycophenolic acid; EC-MPS = enteric coated mycophenolate sodium; SRL = sirolimus; FK778 = immunosuppressant derived from the active metabolite of leflunomide; AbMR = antibody mediated rejection; PRA = panel-reactive antibodies; rATG = rabbit antithymocyte globulin; DGF = delayed graft function; IL2 = interleukin 2; FTY720 = novel sphingosine 1-phosphate receptor modulator; mTORi = mammalian target of rapamycin inhibitor; EVL = everolimus; NSAID

= non steroidal anti inflammatory drugs

* panel reactive antibodies <10%, negative T and B cell cross-match, and negative donor-specific flow cytometry cross-match

27 rejection

Acute rejection 32 TAC, MMF

afterwards

No corticosteroids from transplantation plus rATG 1.5mg/kg IV intraoperatively then 0.9mgkg IV for 5 days versus oral prednisone 20mg daily through month 3, then tapered 2.5mg monthly until 10mg alternate daily plus rATG 1.5mg/kg IV intraoperatively

Heart transplant with low Heart risk^*; 0

Yamani et al,¹²⁰2008

(19)

Table S2. GRADE Evidence Profile for Effects of Interventions to Prevent Non Melanoma Skin Cancer in Solid Organ Transplant Recipients

Comparison Outcome Number of Quality Assessment

participants (Number of trials)

Study limitations (Decrease in Quality Score) Consistency (Decrease in Quality Score);

I²; p-value

Directness (Decrease in Quality Score)

Precision (Decrease in Quality Score)

Publication Bias (Decrease in Quality Score) Cancer-specific interventions

Acitretin Non melanoma skin cancer 61 (2 RCT) Some limitations; inability to combine trial data Not estimable (-1) Direct Imprecise (-1) Insufficient trials

versus due to different trial design to assess

placebo or no Clearance of keratotic skin lesion 38 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial treatment Graft function assessed by mean change 38 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial

in serum creatinine

Serum cholesterol and triglyceride levels 61 (2 RCT) Some limitations; inability to combine trial data Not estimable (-1) Indirect (-1) Imprecise (-1) Insufficient trials

due to different trial design to assess

Acitretin (high Non melanoma skin cancer 26 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial dose) versus Clearance of keratotic skin lesion 26 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial Acitretin (low Graft function assessed by mean change 26 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial dose) in serum creatinine

Liver function, serum cholesterol and 26 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial triglyceride levels

Imiquimod Non melanoma skin cancer 20 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus Clearance of keratotic skin lesion 63 (2 RCT) Some limitations; inability to combine trial data Not estimable (-1) Indirect (-1) Imprecise (-1) Insufficient trials

placebo due to differences in outcome reporting to assess

Graft function assessed by mean change 20 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial in serum creatinine

All-cause mortality 63 (2 RCT) Some limitations; allocation concealment: 2 trials; Moderate Direct Imprecise (-1) Insufficient trials

outcome assessment blinding: 1 trial; ITT inconsistency; to assess

analysis: 1 trial; incomplete follow-up: 2 trials 32%; 0.23

Local skin reactions 62 (2 RCT) Some limitations; allocation concealment: 2 trials; No inconsistency; Direct Imprecise (-1) Insufficient trials

outcome assessment blinding: 1 trial; ITT 0%; 0.91 to assess

(20)

analysis: 1 trial; incomplete follow-up: 2 trials

Nicotinamide Non melanoma skin cancer 60 (2 RCT) Serious limitations (-1); allocation concealment: 1 Moderate Direct Imprecise (-1) Insufficient trials

versus trials; outcome assessment blinding: 1 trial; ITT inconsistency; to assess

placebo or no analysis: 1 trial; incomplete follow-up: 1 trial 56%; 0.13

treatment Clearance of keratotic skin lesion 38 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial Graft function assessed by mean change 22 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial in serum creatinine or albuminuria

Photodynamic Non melanoma skin cancer 93 (3 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Direct Imprecise (-1) Insufficient trials

therapy trials; outcome assessment blinding: 1 trial; ITT 0%; 0.81 to assess

versus analysis: unclear; incomplete follow-up: 2 trials

placebo or no Clearance of keratotic skin lesion 89 (2 RCT) Serious limitations (-1): allocation concealment: 1 Significant Indirect (-1) Imprecise (-1) Insufficient trials

treatment trial; outcome assessment blinding: 1 trial; ITT inconsistency (-1); to assess

analysis: unclear; incomplete follow-up: 0 trials 86%; 0.007

New keratotic skin lesions 53 (2 RCT) Serious limitations (-1): allocation concealment: 0 No important Indirect (-1) Precise Insufficient trials trials; outcome assessment blinding: 1 trial; ITT inconsistency; to assess analysis: unclear; incomplete follow-up: 1 trial 16%; 0.27

Pain at treatment site 95 (4 RCT) Serious limitations (-1): allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

trial; outcome assessment blinding: 1 trial; ITT 0%; 0.85 to assess

analysis: unclear; incomplete follow-up: 2 trials

Photodynamic Non melanoma skin cancer 81 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial therapy Clearance of keratotic skin lesion 89 (2 RCT) Serious limitations (-1): allocation concealment: 0 Significant Indirect (-1) Imprecise (-1) Insufficient trials

versus other trials; outcome assessment blinding: 0 trials; not inconsistency (-1); to assess

treatments ITT analysis: 1 trial, unclear in 1 trial; incomplete 72%; 0.06

follow-up: 1 trial

New keratotic skin lesions 81 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial Pain at treatment site 81 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Topical Non melanoma skin cancer 32 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial NSAID versus Clearance of keratotic skin lesion 32 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial placebo New keratotic skin lesion 32 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial Local skin reaction 32 (1 RCT Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Selenium Skin cancer 184 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus New keratotic skin lesion 184 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial

(21)

Immunosuppression or other interventions

ACE inhibitor Non melanoma skin cancer 295 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus Graft function assessed by mean change 295 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial placebo in eGFR or albuminuria

All-cause mortality 295 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 295 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Acute kidney injury 295 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial AZA versus Non melanoma skin cancer 62 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial CYA Graft function assessed by serum 62 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial

creatinine

Graft loss 62 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 62 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial AZA versus Non melanoma skin cancer 489 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial CYA and Non skin cancer or melanoma 489 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial prednisone

versus CYA withdrawal to AZA and prednisone

Belatacept Non melanoma skin cancer 1573 (5 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Direct Imprecise (-1) Insufficient trials

versus CNI trials; outcome assessment blinding: 5 trials; ITT 0%; 0.91 to assess

analysis: 5 trials; incomplete follow-up: 4 trials

Graft function assessed by end-of-trial 1573 (5 RCT) Serious limitations (-1); allocation concealment: 0 Significant Indirect (-1) Precise Insufficient trials

eGFR trials; outcome assessment blinding: 5 trials; ITT inconsistency (-1); to assess

analysis: 5 trials; incomplete follow-up: 4 trials 89%; <0.001

Acute rejection 1573 (5 RCT) Serious limitations (-1); allocation concealment: 0 Moderate Direct Imprecise (-1) Insufficient trials trials; outcome assessment blinding: 5 trials; ITT inconsistency; to assess analysis: 5 trials; incomplete follow-up: 4 trials 53%; 0.07

Graft loss 1573 (5 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Direct Imprecise (-1) Insufficient trials

trials; outcome assessment blinding: 5 trials; ITT 0%; 0.57 to assess

analysis: 5 trials; incomplete follow-up: 4 trials placebo

(22)

All-cause mortality

Cardiovascular events or mortality

Serious infection

Post transplant lymphoproliferative

1573 (5 RCT)

794 (2 RCT)

1573 (5 RCT)

Serious limitations (-1); allocation concealment: 0 trials; outcome assessment blinding: 5 trials; ITT analysis: 5 trials; incomplete follow-up: 4 trials Serious limitations (-1); allocation concealment: 0 trials; outcome assessment blinding: 2 trials; ITT analysis: 2 trials; incomplete follow-up: 2 trials Serious limitations (-1); allocation concealment: 0 trials; outcome assessment blinding: 5 trials; ITT analysis: 5 trials; incomplete follow-up: 4 trials Serious limitations (-1); allocation concealment: 0

No inconsistency;

0%; 0.50 Moderate inconsistency;

64%; 0.10 Moderate inconsistency;

54%; 0.07 Moderate

Direct

Imprecise (-1)

Insufficient trials to assess Insufficient trials to assess Insufficient trials to assess Insufficient trials disorder

Non skin cancer or melanoma 1573 (5 RCT)

trials; outcome assessment blinding: 5 trials; ITT analysis: 5 trials; incomplete follow-up: 4 trials Serious limitations (-1); allocation concealment: 0

inconsistency;

47%; 0.15

No inconsistency; Direct Imprecise (-1)

to assess Insufficient trials trials; outcome assessment blinding: 5 trials; ITT

0%; 0.45 to assess

FK778 versus Non melanoma skin cancer 46 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial reduction in

immunosuppression

Graft function assessed by end-of-trial eGFR

Acute rejection

46 (1 RCT) 46 (1 RCT)

Some limitations; single trial Some limitations; single trial

Not estimable (-1) Not estimable (-1)

Indirect (-1) Direct

Imprecise (-1) Imprecise (-1)

Single trial Single trial Graft loss 46 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 46 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 46 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Change in BK viral load 46 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial Bortezomib Non melanoma skin cancer 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus

placebo

Graft function assessed by end-of-trial creatinine clearance or serum creatinine Late antibody-mediated rejection

44 (1 RCT) 44 (1 RCT)

Single trial Single trial Graft loss 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Peripheral neuropathy 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Gastrointestinal adverse events 44 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial

(23)

CYA high Non melanoma skin cancer 231 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial dose versus Graft function assessed by end-of-trial 231 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial CYA low dose creatinine clearance or serum creatinine

Acute rejection 231 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Graft loss 231 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 231 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 231 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 231 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial CYA early Non melanoma skin cancer 203 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus CYA Graft function assessed by end-of-trial 203 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial late creatinine clearance

Acute rejection 203 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Graft loss 203 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 203 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 203 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 203 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial TAC versus Skin cancer 2178 (6 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Direct Imprecise (-1) Insufficient trials

CYA trials; outcome assessment blinding: 1 trial; ITT 0%; 0.57 to assess

Graft function assessed by end-of-trial 580 (2 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Indirect (-1) Imprecise (-1) Insufficient trials

eGFR trials; outcome assessment blinding: 0 trials; ITT 0%; 0.86 to assess

Acute rejection 2160 (6 RCT) Serious limitations (-1); allocation concealment: 0 Moderate Direct Precise Insufficient trials trials; outcome assessment blinding: 1 trial; ITT inconsistency; to assess analysis: 4 trials; incomplete follow-up: 5 trials 42%; 0.13

Graft loss 1776 (4 RCT) Serious limitations (-1); allocation concealment: 0 No important Direct Imprecise (-1) Insufficient trials trials; outcome assessment blinding: 1 trial; ITT inconsistency; to assess analysis: 2 trials; incomplete follow-up: 4 trials 3%; 0.35

All-cause mortality 2059 (6 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Direct Imprecise (-1) Insufficient trials

trials; outcome assessment blinding: 1 trial; ITT 0%; 0.52 to assess

Cardiovascular mortality 1490 (4 RCT) Serious limitations (-1); allocation concealment: 0 No inconsistency; Direct Imprecise (-1) Insufficient trials

trials; outcome assessment blinding: 1 trial; ITT 0%; 0.65 to assess

Infection 2118 (5 RCT) Serious limitations (-1); allocation concealment: 0 Significant Direct Imprecise (-1) Insufficient trials

(24)

Non skin cancer 2178 (6 RCT)

trials; outcome assessment blinding: 1 trial; ITT analysis: 3 trials; incomplete follow-up: 5 trials Serious limitations (-1); allocation concealment: 0

inconsistency (-1);

84%; <0.001

No inconsistency; Direct Imprecise (-1)

to assess Insufficient trials

Hypertension 2118 (5 RCT)

0%; 0.71

Significant Direct Imprecise (-1)

Dyslipidemia 1879 (4 RCT)

inconsistency (-1);

93%; <0.001

New-onset diabetes mellitus 2043 (6 RCT)

inconsistency (-1);

63%; 0.04

Renal function assessed by end-of-trial 630 (3 RCT)

inconsistency (-1);

87%; <0.001

Significant Indirect (-1) Imprecise (-1)

to assess Insufficient trials serum creatinine trials; outcome assessment blinding: 1 trial; ITT

inconsistency (-1);

84%; 0.002

to assess

CYA + MMF Skin cancer 440 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus TAC

high dose + SRL low dose

Graft function assessed by end-of-trial creatinine clearance or serum creatinine Acute rejection

440 (1 RCT) 440 (1 RCT)

Single trial Single trial versus TAC Graft loss 440 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial low dose + All-cause mortality 440 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial SRL high Cardiovascular events 440 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial dose New-onset diabetes mellitus 440 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial TAC standard Non melanoma skin cancer 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial dosing versus Acute rejection 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial dosing by Graft loss 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial CYP3A5 All-cause mortality 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial genotype Infection 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Cardiovascular events 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 240 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Alemtuzumab Skin cancer 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus Graft function assessed by end-of-trial 501 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial

(25)

conventional serum creatinine

induction Acute rejection 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial therapy Graft loss 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Cardiovascular events 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer 501 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Anti-CD2 Non melanoma skin cancer 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus no Graft function assessed by end-of-trial 40 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial treatment liver function tests

Acute rejection 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Graft loss 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Cardiovascular mortality 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 40 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Basiliximab Skin cancer 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus Graft function assessed by end-of-trial 212 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial daclizumab eGFR

Acute rejection 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Graft loss 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Cardiovascular mortality 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer 212 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Anti-IL2 Non melanoma skin cancer 353 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

versus trial; outcome assessment blinding: 1 trial; ITT 0%; 0.96 to assess

placebo or no analysis: 1 trial; incomplete follow-up: 1 trial

treatment Graft function assessed by end-of-trial 298 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial serum creatinine

Acute rejection 353 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Precise Insufficient trials

analysis: 1 trial; incomplete follow-up: 1 trial

Renal graft loss 353 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

(26)

trial; outcome assessment blinding: 1 trial; ITT 0%; 0.81 to assess analysis: 1 trial; incomplete follow-up: 1 trial

All-cause mortality 353 (2 RCT) Serious limitations (-1); allocation concealment: 1 Moderate Direct Imprecise (-1) Insufficient trials trial; outcome assessment blinding: 1 trial; ITT inconsistency; to assess analysis: 1 trial; incomplete follow-up: 1 trial 63%; 0.10

Infection 353 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

analysis: 1 trial; incomplete follow-up: 1 trial

Cardiovascular events or mortality 353 (2 RCT) Serious limitations (-1); allocation concealment: 1 Moderate Direct Imprecise (-1) Insufficient trials trial; outcome assessment blinding: 1 trial; ITT inconsistency; to assess analysis: 1 trial; incomplete follow-up: 1 trial 32%; 0.23

Non skin cancer or melanoma 298 (1 RCT) Some limitations; single trial with events Not estimable (-1) Direct Imprecise (-1) Single trial Anti-CD40 Non melanoma skin cancer 138 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus Graft function assessed by end-of-trial 138 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial standard care eGFR

Acute rejection 138 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Graft loss 138 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 138 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 138 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial rATG single Non melanoma skin cancer 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial dose versus Graft function assessed by end-of-trial 95 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial rATG double eGFR

dose Acute rejection 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Graft loss 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Cardiovascular events 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Non skin cancer or melanoma 95 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial rATG versus Non melanoma skin cancer 213 (2 RCT) Very serious limitations (-2); allocation No important Direct Imprecise (-1) Insufficient trials

anti-IL2 concealment: 0 trials; outcome assessment inconsistency; to assess

blinding: 0 trials; ITT analysis: 2 trial; incomplete 21%; 0.26 follow-up: 1 trial

Acute rejection 213 (2 RCT) Very serious limitations (-2); allocation Moderate Direct Imprecise (-1) Insufficient trials

concealment: 0 trials; outcome assessment inconsistency; to assess

(27)

blinding: 0 trials; ITT analysis: 2 trial; incomplete 46%; 0.17 follow-up: 1 trial

Graft loss 183 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial All-cause mortality 213 (2 RCT) Very serious limitations (-2); allocation No inconsistency; Direct Imprecise (-1) Insufficient trials

concealment: 0 trials; outcome assessment 0%; 0.99 to assess

blinding: 0 trials; ITT analysis: 2 trial; incomplete follow-up: 1 trial

Infection 213 (2 RCT) Very serious limitations (-2); allocation No inconsistency; Direct Precise Insufficient trials

blinding: 0 trials; ITT analysis: 2 trial; incomplete follow-up: 1 trial

Non skin cancer or melanoma 183 (1 RCT) Some limitations; single trial with events Not estimable (-1) Direct Imprecise (-1) Single trial rATG versus Non melanoma skin cancer 344 (2 RCT) Serious limitations (-1); allocation concealment: 1 Moderate Direct Imprecise (-1) Insufficient trials

no treatment trial; outcome assessment blinding: 0 trials; ITT inconsistency; to assess

or placebo analysis: 1 trial; incomplete follow-up: 2 trials 69%; 0.07

Acute rejection 346 (2 RCT) Serious limitations (-1); allocation concealment: 1 Significant Direct Imprecise (-1) Insufficient trials trial; outcome assessment blinding: 0 trials; ITT inconsistency (-1); to assess analysis: 1 trial; incomplete follow-up: 2 trials 80%; 0.02

Graft loss 346 (2 RCT) Serious limitations (-1); allocation concealment: 1 No important Direct Imprecise (-1) Insufficient trials trial; outcome assessment blinding: 0 trials; ITT inconsistency; to assess analysis: 1 trial; incomplete follow-up: 2 trials 1%; 0.31

All-cause mortality 346 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

trial; outcome assessment blinding: 0 trials; ITT 0%; 0.65 to assess

CMV Infection 346 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

Cardiovascular events or mortality 346 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Precise Insufficient trials

Non skin cancer or melanoma 344 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

Sphingosine Graft function assessed by end-of-trial 261 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Single trial 1-phosphate eGFR

(28)

receptor Acute rejection 261 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial modulators Graft loss 261 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial versus MMF All-cause mortality 261 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Infection 261 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial Cardiovascular events 261 (1 RCT) Some limitations; single trial Not estimable (-1) Direct Imprecise (-1) Single trial MMF versus Skin cancer 959 (3 RCT) Serious limitations (-1); allocation concealment: 2 No inconsistency; Direct Imprecise (-1) Insufficient trials

AZA trials; outcome assessment blinding: 0 trials; ITT 0%; 0.95 to assess

Graft function assessed by end-of-trial 487 (3 RCT) Serious limitations (-1); allocation concealment: 1 Moderate Indirect Imprecise (-1) Insufficient trials

eGFR trial; outcome assessment blinding: 0 trials; ITT inconsistency; to assess

analysis: 3 trials; incomplete follow-up: 2 trials 58%; 0.09

Acute rejection 354 (2 RCT) Very serious limitations (-2); allocation No inconsistency; Direct Imprecise (-1) Insufficient trials

blinding: 0 trials; ITT analysis: 2 trials; incomplete follow-up: 1 trial

Graft loss 1065 (4 RCT) Serious limitations (-1); allocation concealment: 2 Moderate Direct Imprecise (-1) Insufficient trials trials; outcome assessment blinding: 0 trials; ITT inconsistency; to assess analysis: 3 trials; incomplete follow-up: 3 trials 32%; 0.22

All-cause mortality 1065 (4 RCT) Serious limitations (-1); allocation concealment: 2 No important Direct Precise Insufficient trials trials; outcome assessment blinding: 0 trials; ITT inconsistency; to assess analysis: 3 trials; incomplete follow-up: 3 trials 3%; 0.38

Infection 932 (3 RCT) Serious limitations (-1); allocation concealment: 1 Significant Direct Imprecise (-1) Insufficient trials trials; outcome assessment blinding: 0 trials; ITT inconsistency (-1); to assess analysis: 2 trials; incomplete follow-up: 2 trials 72%; 0.03

Cardiovascular events or mortality 682 (2 RCT) Serious limitations (-1); allocation concealment: 1 Significant Direct Imprecise (-1) Insufficient trials trials; outcome assessment blinding: 0 trials; ITT inconsistency (-1); to assess analysis: 1 trials; incomplete follow-up: 1 trials 79%; 0.03

Non skin cancer 1065 (4 RCT) Serious limitations (-1); allocation concealment: 2 Moderate Direct Imprecise (-1) Insufficient trials trials; outcome assessment blinding: 0 trials; ITT inconsistency; to assess analysis: 3 trials; incomplete follow-up: 3 trials 25%; 0.26

MMF versus Non melanoma skin cancer 745 (2 RCT) Serious limitations (-1); allocation concealment: 1 No inconsistency; Direct Imprecise (-1) Insufficient trials

EC-MPS trial; outcome assessment blinding: 0 trials; ITT 0%; 0.98 to assess

Graft function assessed by end-of-trial 322 (1 RCT) Some limitations; single trial Not estimable (-1) Indirect (-1) Imprecise (-1) Insufficient trials

serum creatinine to assess

Table of contents

Table of contents

Appendix S1. Electronic search strategies

Table S1. Participant Characteristics and Interventions to Prevent Non Melanoma

Skin Cancer in Randomized Controlled Trials of Solid Organ Transplant Recipients

Table S2. GRADE Evidence Profile for Effects of Interventions to Prevent Non

Melanoma Skin Cancer in Solid Organ Transplant Recipients

1 exp Organ Transplantation/

1 (organ near/3 transplant*):ti,ab,kw

5 (lung near/2 (transplant* or graft* or allograft*)):ti,ab,kw

9 ("basal cell" near/2 carcinoma*):ti,ab,kw

13 {or 8-12}

3 ((kidney or renal) adj3 (transplant* or graft* or allograft*)).tw.

7 (pancreas adj3 (transplant* or graft* or allograft*)).tw.

Appendix S1. Electronic search strategies

Cochrane Central Register of Controlled Trials (CENTRAL) 04/04/2018, 136 citations

# Searches

2 (heart near/3 (transplant* or graft* or allograft*)):ti,ab,kw 4 (liver near/2 (transplant* or graft* or allograft*)):ti,ab,kw 6 (pancreas near/3 (transplant* or graft* or allograft*)):ti,ab,kw

8 (skin near/2 (cancer* or neoplasm* or tumor* or tumour* or malignan* or lesion*)):ti,ab,kw

10 ("squamous cell" near/2 carcinoma*):ti,ab,kw 12 (actinic near/2 keratos*):ti,ab,kw

14 {and 7, 13}

MEDLINE 04/04/2018, 587 citations

# Searches

2 (organ adj3 transplant*).tw.

4 (liver adj2 (transplant* or graft* or allograft*)).tw.

6 (heart adj3 (transplant* or graft* or allograft*)).tw.

8 or/1-7

10 exp Carcinoma, Basal Cell/

9 exp Skin Neoplasms/

5 (lung adj2 (transplant* or graft* or allograft*)).tw.

11 (BCC or SCC):ti,ab,kw 7 {or 1-6}

3 ((kidney or renal) near/3 (transplant* or graft* or allograft*)):ti,ab,kw

1 organ transplantation/

13 (skin adj2 (cancer* or neoplasm* or tumor* or tumour* or malignan* or lesion*)).tw.

17 actinic keratos*.tw.

21 controlled clinical trial.pt.

25 drug therapy.fs.

29 Cross-over Studies/

33 31 not 32

3 exp kidney transplantation/

7 (organ adj3 transplant*).tw.

12 Keratosis, Actinic/

14 basal cell carcinoma*.tw.

16 (SCC or BCC).tw.

18 or/9-17

20 randomized controlled trial.pt.

22 pragmatic clinical trial.pt.

24 placebo.ab.

26 randomly.ab.

28 groups.ab.

30 (crossover or cross-over).tw.

32 animals/ not (humans/ and animals/) 34 and/19,33

Embase 04/04/2018, 293 citations

# Searches

2 exp heart transplantation/

4 exp liver transplantation/

6 exp pancreas transplantation/

5 exp lung transplantation/

31 or/20-30 27 trial.ab.

23 randomized.ab.

19 and/8,18

15 squamous cell carcinoma*.tw.

11 exp Carcinoma, Squamous Cell/

9 (liver adj2 (transplant* or graft* or allograft*)).tw.

13 or/1-12

17 actinic keratosis/

21 (SCC or BCC).tw.

25 randomized controlled trial/

29 random$.tw.

33 (double$ adj blind$).tw.

37 or/25-36

8 ((kidney or renal) adj3 (transplant* or graft* or allograft*)).tw.

10 (lung adj2 (transplant* or graft* or allograft*)).tw.

12 (pancreas adj3 (transplant* or graft* or allograft*)).tw.

14 skin cancer/

16 exp non melanoma skin cancer/

18 (skin adj2 (cancer* or neoplasm* or tumor* or tumour* or malignan* or lesions)).tw.

20 squamous cell carcinoma*.tw.

22 actinic keratos*.tw.

24 and/13,23

2 (heart near/3 (transplant* or graft* or allograft)):ti,ab,kw 4 (liver near/2 (transplant or graft* or allograft)):ti,ab,kw 6 (pancreas near/3 (transplant or graft* or allograft*)):ti,ab,kw

10 ("squamous cell" near/2 carcinoma):ti,ab,kw 12 (actinic near/2 keratos):ti,ab,kw