Tab le S1. Demo grap hic charact eristi cs an d k e y cli ni cal ou tco mes of inclu ded kidn e y tran spl ant stu d y reci pients.
Tab le S2. Summ ar y catego ries of biopsi es b y in fl amm ation (i-INT).
Tab le S3. Anteced en t cli ni cal caus es o f i-INT b y GEE.
Tab le S4. Con fi rm at or y anal ysi s I. Hist ol o gi cal d et ermi n ants of Ban ff i sco res usin g o rdi nal regres sion o f hi stol o gi cal ris k fact ors on l y.
Tab le S5. Hi stolo gi cal predi ct ors int erstit ial i nflamm ati on b y GEE.
Table S6. Con fi rm at or y anal ysi s II: Det ermin ant s o f i nflamm atio n s co res usin g o rdin al regress ion of cli ni cal and hi stological ri sk fact ors.
Tab le S7 a. Treatm en t of i -INT episodes accordin g to Banff i s cores.
Tab le S7b . R el ation s hips of treatm ent given, compli ance an d s ubs equ en t rej ectio n i n i -INT cases acco rdi n g t o Banff i s core u sin g lo gis tic regressio n.
Tab le S8. Resolu tion of in fl amm ation in i -INT kid ne ys .
Tab le S9. Cont em po ran eou s p redi ctors o f pro gres siv e intersti ti al fib ro sis b y sequenti al b iop s y s amplin g b y un ivari abl e and mult ivari ab le Cox regres sion . Tab le S10 . In cid ent fibro sis in earl y t rans plantat ion: Subset an al ys is o f effects o f is chemi a-rep erfu sion inj ur y an d i- INT.
Tab le S11 . Cli nical and pat holo gi cal ri sk fact ors for p ro gressi ve fib ro sis:
BKVAN su bs et an al ysis.
Table S12 . Su bs et-an al ys is o f i- INT biops ies an d i nci d ent fibrosis with treatm ent effects i nclud ed i n cox regressi on.
Tab le S13 . Act uari al an al ys is o f th e effects of in fl amm ati on o n d eath - censo red graft s urviv al b y univ ari abl e and multiv ari abl e m od el s.
Tab le S14 . Thres hol d res ults of i -INT b y out com e anal ys is of in cident mod erat e fib ros is an d cumul ati ve graft failure.
Fi gure S 1. Lack o f effect of int erstiti al i nfl amm atio n o n t ubular inj ur y from isch emi a-rep erfusio n inju r y. Three m od el s.
Table S1. Ke y demo graphi c characterist i cs of inclu ded p ati en ts (n=775 ).
Patien t da ta
Recipi ent age ( years ) 46.7 ±12.9 Recipi ent s ex (n , % mal e) 473 (6 1.0 %) Caus es of end -s ta ge renal failure:
Glom erulo neph ritis 220 (2 8.4%) Diabetic neph ro p ath y 314 (4 0.5%) In t erstiti al neph ritis 5 (0.6 %) H ypertensiv e n eph ro scl erosis 31 (4.0%) Pol yc ys ti c ren al dis eas e 63 (8.1%) Reflux d ys pl asti c s yndrome 63 (8.1%)
Oth er / unk nown 79 (10.2%)
Transpl antati on d emog raphi cs :
Deceased d ono r (n , %) 589 (76.0 %) Don or age ( years ) 40.8±17 .0 Don or male (n, %) 414 (53.4 %) Cold i schem ic tim e (hou rs ) 9.1± 4.3 HLA mism at ch (score o f 6) 3.8± 1.7
Kidn e y / kidn e y-p an creas trans pl ant reci pient 515 / 260
An y p ret rans pl ant DSA 205/715 of av ail abl e results (28.7%) Induction i mmunos uppression :
Non e 86 (11.1%)
Basilix um ab 630 (8 1.3 %)
Anti -l ym pho c yt e glo bulin 52 (6. 7%) Desensitiz atio n / ABOi 7 (0.9 %) Earl y clini cal outco mes:
Del a yed graft fun cti on 101 (1 3.0%) Earl y acut e cell ular rej ect ion 96 (12 .3 %) Earl y vas cul ar rej ect ion 11 (1.4%) Earl y hum oral rej ect ion 34 (4.4%)
Table S 2a. S umm ar y cat ego ri es of biopsi es (n=205 5) b y infl ammati on (i -INT, Ban ff i≥1). A two sample t-test with common variance or Wilcoxon rank sum test , for p aram et ri c and nonp aramet ri c dat a, resp ectiv el y was u sed .
Pretransplan t fa cto rs i0 i-I NT P va lue
Bio psi es (n umb er) 1681 374
Recipi ent age ( years ) 47.4±12.4 46.2±13.9 0.10 8 Recipi ent male (N, %) 1042 (62. 0%) 225 (6 0.2 %) 0.49 8 Kidn e y/ kid ne y-p ancreas 1156/ 525 258/116 0.88 0
HLA mism at ch 3.8±1.7 3.9±1.7 0.12 8
An y p ret rans pl ant DSA (M FI ≥500 by solid phase testing)
536 (3 1.9 %) 121 (3 2.4 %) 0.86 0 Deceased/liv in g do n or 1314/ 367 269/1 05 0.03 9 Don or age ( years ) 42.2±17 .0 42.0±17 .2 0.95 2 Don or male (n, %) 881 (52.4 %) 183 (48.8 %) 0.23 5 Cold i schem ic tim e (hou rs ) 9.0± 4.2 8.5± 4.4 0.01 8 Warm is ch emi a (>10 min) 183 (10.9 %) 37 (9. 8%) 0.55 8
In d uct ion th erap y (%) 1566 (93.2%) 350 (93.6 %) 0.94 9
Non e 115 24
Basilix um ab 1391 307
Anti -l ym pho c yt e glo bulin 131 25
Desensitiz atio n / ABOi 22 14
Earl y events within 3 months pos ttrans planta tion (p rior to biopsy) Del a yed fun ctio n (%) 242 (1 4.3 %) 67 (17 .9 %) 0.0 59 Cellul ar rejecti on (%) 246 (1 4.6 %) 120 (3 2.1 %) <0. 001 Antib od y rej ectio n (%) 92 (5.5%) 48 (12.8 %) <0. 001 Vascular rej ect ion (%) 15 (3.0%) 18 (4.8%) 0.0 87
Therapy recei ved b efore b iopsy :
Table S2b.
Med icati ons at biop sy i0 i-I NT P va lue
Tacrolim us d os e (m g/da y) 6.8±4.4 7.0±4.2 0.4 81 Tacrolim us l ev el (n g /ml) 8.5±3.6 8.8±4.8 0.2 45 C ycl ospo ri ne do se (mg/d a y) 217±116 231±127 0.4 84 C ycl ospori ne lev el (n g/ml ) 186±147 194±166 0.7 68 M ycoph en ol ate mo fetil (g/d ) 1.83±0. 37 1.79±0. 41 0.1 54 M ycoph en ol ate so diu m (g/d ) 1.27±0. 26 1.30±0. 26 0.4 96 Prednis olon e dos e (g /da y) 14.1±6. 0 15.7±7. 2 <0. 001
Histologi ca l co mpa rison
Facto r i0 i-I NT P va lue
Months p ostt ransp lant 18.9 ±4 4.0 19.3±37 .2 0.8 96 Indi catio n b iop s y (n, %) 372 (22.1 %) 186 (49.7 %) <0. 001 Creati nin e (um ol/ L) 158±134 234±184 <0. 001
Glom eruli (n umb er) 11.3±6. 4 12.1±7. 5 0.0 30
Banff g score 0.04±0.24 0.23±0. 57 <0. 001
Ban ff i s co re 0.0±0.0 1.51±0. 68 <0. 001
Ban ff t s co re 0.24±0. 73 1.32±0. 73 <0. 001
Ban ff v score 0.01±0. 14 0.10±0. 37 <0.001
Ban ff pt c s core 0.05±0. 28 0.54±0. 86 <0. 001
Ban ff ti score 0.29±0. 59 1.67±0. 88 <0. 001
Ban ff i- IFTA score 0.88±0.87 1.65±0. 91 <0. 001 Ban ff ci s co re 0.71±0. 87 1.15±1. 02 <0. 001
Ban ff ct s co re 0.82±0. 82 1.19±0. 98 <0. 001
Ban ff cv s co re 0.41±0.68 0.36±0. 68 0.1 99
Ban ff cg s co re 0.05±0.29 0.12±0. 42 <0.001
Ban ff ah s co re 0.49±0. 76 0.46±0.77 0.296
SV40T positi ve (n, %) 22 (1.3%) 52 (13.9 %) <0.001
C4d s cores 0.10±0.39 0.30±0.67 <0.001
Table S2c. Ci rcul ati ng DS A results a t the ti me of biops y
Facto r i0 i-I NT P va lue
Numb er of biop si es 1681 374
DSA resul t av ail abl e 1125 (66. 9%) 270 (72.2 %) No DSA d et ect ed 681 (60.5 %) 133 (49.3 %)
DSA pres en t (M FI≥500) 444 (39.5 %) 137 (50.7 %) <0. 001
Class I 157 (23.1 %) 35 (13 .0 %)
Class II 237 (34.8 %) 79 (29 .3 %)
Class es I & II 50 (7.3%) 23 (8. 5%) 0.206
Mean M FI (nil DSA as 0) 996±254 8 2430±46 13 <0. 001
Medi an M F I (IQR ) 0 (0-923 ) 0 (0-267 3)
Mean M FI (DSA onl y) 2550±3560 4897±55 56 <0. 001 Medi an M F I (IQR ) 1200 (767 -2 435 ) 2673 (927 -7 281 )
Fo otno tes: DSA don or sp eci fi c ant ibo d y; M FI medi an flu ores cen ce int ens it y (of th e immu nod omi nan t DS A). M icro vas cul ar in fl amm atio n d efi n ed as Banff g+ptc≥2. Mean±SD and m edi an±IQR (int erquartil e ran ge) for contin uou s vari abl es. Catego rical v ari abl es : abs olut e numb er and frequ en cies.
Table S2d. Princip a l clini co-pathologi cal diagnosis :
Facto r i0 i-I NT P va lue
Numb er of biop si es 1681 374
Months p ostt ransp lant 18.9±44.0 19.2±37 .1 0.8 96 Medi an ( IQR, m ont h s) 3 (1-12) 5 (1-18. 5) 0.6 65
Subcl ini cal rej ectio n 3 (0.2 %) 102 (27.5 %) <0. 001
Bo rd erlin e TCMR 0 88
Ban ff Ia/ Ib TCMR 0 7
Ban ff II TCMR 1 4
AMR 2 (0 v as cul ar) 3 (0 v as cul ar)
Acute rej ectio n (tot al) 16 (1.0%) 129 (37.2 %) <0. 001
Bord erlin e TCMR 0 46
Banff Ia/ Ib TCMR 0 47
Ban ff II TCMR 4 12
AMR 12 (1 vascul ar) 24 (11 v as cul ar)
Chro ni c AMR 30 (1.8%) 16 (4. 3%) <0. 01
Chro ni c TC MR 8 (0.5 %) 5 (1.3 ) <0. 01
Su mmated rejecti on (n, % ) 57 (3. 4% ) 252 (6 7.4%) c <0.0 01
BKVAN 22 (1.3%) 37 (9.9%) <0. 001
Acute tu bul ar n ecro s is 190 (11.3 %) 22 (5. 9%) 0.002 IF/TA (no s) 620 (36.9 %) 54 (14 .4 %) <0. 001 Glom erulo neph ritis 19 (1.1%) 1 (0.3 %) <0. 001 CNI n eph rot ox icit y 40 (2.4%) 1 (0.3 %) <0. 001
Oth er 0 (0%) 3 (3.4 %) <0. 001
No rmal / m inim al 733 (43.6 %) 4 (0.8 %) <0.001
Footno tes: AMR, ant ibod y m edi at ed rej ection; BKVAN, BK vi ral allo graft nephropath y; C AMR , chroni c ant ibod y medi at ed rej ection; CNI, cal ci neuri n inhibit or; IF/TA, interstiti al fi brosis and t ubul ar at roph y; TCMR , T cel l
Table S3 a. An tecedent and con temp oran eou s clin ical causes of i-I NT.
Univ ari abl e and m ultiv ariable binomi al gen eralized esti mating equati on (GEE) of caus al ris k fact ors o f int erstit ial infl ammation (Ban ff i≥1, n=2055 biops ies fro m 755 patient s.
OR 95%CI P va lue
Univa riab le ri sk fa cto rs at tran splan tation
Recipi ent age ( years ) 0.99 2 0.9992 -1. 004 0.1 89 Recipi ent s ex mal e 0.886 0.672-1.1 69 0.3 93
Deceased d ono r 0.75 2 0.554-1.0 22 0.0 69
Pret rans pl ant DSA 1.02 8 0.762-1.3 88 0.8 56 HLA mism at ch (of 6 ) 1.071 0.98 1-1.1 69 0.1 27
Earl y pos ttransplan t risks and p rior ev ents
Del a yed graft fun cti on 1.476 1.023-2.1 28 0.0 37 Earl y T cell rej ect io n 1.638 1.169-2.2 96 0.0 04 Earl y v as cul ar rej ect ion 1.046 0.483-2.2 62 0.3 94 Earl y antib od y rej ect ion 1.518 0.89 7-2.5 67 0.1 20 Prio r p uls e co rti cost eroids 1.320 0.983-1.7 73 0.0 65 Prio r antit h ym oc yt e gl obu lin 0.847 0.542-1.3 24 0.4 67
Prior BKVAN 2.31 5 1.378-3.8 91 0.0 02
Prior BK vi remi a 2.011 1.384-2.9 24 <0. 001
At th e ti me of biop s y
Month s p ostt ransp lant 1.00 0 0.99 7-1.0 03 0.9 64 In di catio n (vs p roto col) 3.25 6 2.55 2-4.153 <0. 001 Serum creatin in e ln (umol/ L) 2.500 2.008-3.113 <0. 001 DSA detect ed (M F I≥500) 1.57 4 1.16 6-2.1 25 0.0 03 Tacrolim us (vs c ycl o spo rin e) th erap y
0.44 6 0.30 1-0.6 61 <0.001
Table S3b. An tecedent clini cal causes of i -I NT. Mult ivari able bino mial gen eralized es tim at in g equ atio n (GEE) of ri sk factors of int erstit ial infl amm atio n (Banff i≥1, n=2055 biopsies from 736 patients with complete dat a) aft er b ackward s elim in atio n. M odel s 1 and 2 u sed clini cal ri sks factors with an d witho ut t he i ncorpo ration o f calcin eu rin i nhi bit or t herap y as a sen sitivi t y an al ys is. All i denti fied p redi ct ors rem ained si gnificant .
Preli mina ry cl inical mod el 1: Cl inical risks (with CNI th erapy ex cluded ).
Multiva riabl e ri sk f acto rs OR 95% CI P va lue In di catio n (vs p roto col) 3.250 2.53 2-4.1 73 <0. 001 Earl y T cell rej ect io n (an y) 1.688 1.229-2.3 18 <0. 001 Prio r BKVAN (an y) 2.31 9 1.42 5-3.7 72 <0. 001 HLA mism at ch (of 6 ) 1.09 7 1.00 4-1.198 0.040
Final clini ca l model 2 fo r clini cal ri sks (CNI th erapy in clu ded) Multiva riabl e ri sk f acto rs OR 95%CI P va lue In di cation (vs p roto col) 3.107 2.41 2-4.0 03 <0. 001 Earl y T cell rej ect io n (an y) 1.73 4 1.26 4-2.3 77 <0. 001 Prio r BKVAN (an y) 1.837 1.06 1-3.1 80 0.0 30 HLA mism at ch (of 6 ) 1.101 1.00 9-1.201 0.0 44 Tacrolim us (vs . c ycl ospo rin e) 0.62 8 0.41 7-0.9 44 0.025
Fo otnotes: DSA, d ono r s peci fi c ant ib odi es; BKVAN, BK vi rus allo graft nep hrop ath y; S V40 T, simi an vi rus 40 l arge T anti gen.
Table S4. Confi rmato ry analy sis I : H istol ogi cal d etermi nants of Banff i sco res u sing o rdina l reg ressi on of his tologi cal risk facto rs only . Ordi nal lo gisti c regres sio n treat ed Banff inflammation scores as an o rd ered catego rical valu e, an d comp ared a ran ge of histo lo gi cal explanat or y v ariable (n =20 55 bio psi es ). Th e upp ermos t outpu ts (“const an t”) des cribes th e cum ulat iv e propo rti onal o dds o f the occurren ce o f in fl am matio n, as t he thresh old i s st ep wis e increased to t he wo rse v al ue (i =3 s co re). Th e lo wermo st tabl e of n egati ve coeffi ci ent s an d t he od ds rati o (OR , l es s t han o ne), m easu re the p ro babilit y o f an y valu e fallin g int o a lower tub ulits categor y as t he categor y cut -poi nt is i ncreased (t he n umerato r of t he proportional odds mod el). Gen erall y, n egativ e co effi ci ents decreas e the odds ratio an d in creas e the tend en c y fo r a hi gher cat ego r y.
Mod el 1: Banff infla mma tion score against hi stolog ical para meters.
Fin al parsim oni ous histol o gi cal Model 1 (using onl y Banff hist olo gical vari abl es an d S V40 T and C4d st ain ing). R es ponse is Ban ff in fl amm atio n sco re (d f=201 3, -2 lo g-li kel iho od =16 06.9).
Facto r Co effici ent (±SE) P Value OR (95% CI ) Const ant 0 3.77 8±0 .14 7 <0.001 43.7 26 32.7 8-58. 32 Const ant 1 5.69 4±0 .20 6 <0.001 296. 99 198. 3-444 .9 Const ant 2 8.24 3±0 .33 4 <0.001 3802 .6 1974 .8 -73 21. 9
t score -2. 718±0. 128 <0. 001 0.066 0.051-0.0 85 g s co re -0. 403±0. 160 0.012 0.668 0.489-0.9 14 ptc score -0. 739±0. 107 <0. 001 0.478 0.387-0.5 90 SV40 T s co re -0. 583±0. 203 0.004 0.558 0.375-0.8 32 ATN (an y) -0. 546±0. 153 <0 .001 0.579 0.429-0.7 82
Table S5 . H istol ogi cal predi cto rs inters ti tial infla mma ti on. Lo cal histol o gi cal ri sk factors ass o ciat ed wit h i-INT o n bio ps y (Ban ff i≥1) were ev alu at ed b y u niv ari abl e and multi vari ab le bino mial gen eral ized esti ma tin g equations (n =20 55 fro m 755 p ati ents, to det erm in e the in tra-ren al rel ati ons hips b etween p atholo gi cal alt erations and i - INT.
Univa riab le ri sk fa cto rs OR 95%CI P va lue Glom eruli (n umb er) 1.01 4 0.997-1.0 32 0.0 09
Ban ff g score 3.667 2.545-5.2 84 <0. 001
Ban ff t s co re 21.3 3 15.2 9-29. 77 <0. 001
Ban ff v score 5.120 2.439-10.75 <0. 001
Ban ff ah s co re 0.90 4 0.75 9-1.0 77 0.2 60 Ban ff pt c s core 4.198 3.32 3-5.3 03 <0.001 Ban ff ci s co re 1.584 1.393-1.8 01 <0. 001 Ban ff ct s co re 1.560 1.358-1.793 <0. 001 Ban ff cv s co re 0.89 8 0.73 6-1.0 97 0.292 Ban ff cg s co re 1.687 1.244-2.2 88 <0. 001
C4d s co re 1.958 1.53 2-2.5 02 <0. 001
SV40T s co re 5.29 2 3.39 1-8.2 60 <0.001 Acute tu bul ar necro s is (an y) 2.431 1.84 7-3.2 01 <0. 001
Multiva riabl e ri sk f acto rs OR 95% CI P va lue Ban ff t s co re 17.791 12.5 44 -25.23 2 <0. 001
Ban ff g score 1.74 5 1.18 9-2.5 62 0.0 04
Ban ff pt c s core 2.56 0 1.95 6-3.3 50 <0. 001
SV40 T s co re 2.52 7 1.35 0-4.729 0.004
Acute tu bul ar necro s is (an y) 1.81 8 1.27 0-2.6 01 <0. 001
Fo otnotes: Univ ariable an d mult iv ari able l ogis tic regress ion res ults are express ed as od ds rat io (OR ) an d 9 5% confid en ce i nterval (C I). SV40 T, simian vi ru s T anti gen.
Table S6 . Confi rma to ry an alysi s II : Determinan ts of infla mma ti on s cores using o rdinal reg ressi on of clinical a nd histol ogi cal ri s k factors. Final parsim onio us histol o gi cal/ cli ni cal risk fact ors in th e p redi ction o f Ban ff i sco res i ncorpo rat ed ab ov e hi stologi cal vari abl es (from Mod el 1 ) with add ition al clini cal v ari ables s uch as: inclu din g indicati on (versu s prot ocol ) biopsy, early (≤3 months post transplant) T cell-mediated rejection. Response is Banff i nflam mat i on s co re, an d the fi nal multi vari abl e m odel is pres ented (d f=199 4, -2l o g-lik el ihood was 15 82. 4).
To summ arize, th e i sco re cat egor y was rel ativ el y redu ced b y prot ocol bi ops y stat us an d pri or earl y TCMR, when adjust ed for histolo gi cal find in gs.
Tacrolim us (v ersu s cycl ospo ri ne) th erap y, HLA mi smatch, an d p ast BKVAN, lost t hei r si gn ifi can ce i n th e m ulti vari abl e m odel.
Mod el 2 : Fin al p arsi moni ous mod el of Banff i scores inco rpo ratin g clini cal and his to lo gical risk fa cto rs.
Facto r Co effici ent (±SE) P Value Odds rati o (95% CI )
Const ant 0 3.91 4±0 .15 4 <0.001 50.0 91 37.0 06 -67 .80 2 Const ant 1 5.85 2±0 .21 4 <0.001 347. 97 228. 82 -52 9.1 7 Const ant 2 8.41 2±0 .34 1 <0. 001 4501.3 2307.5 -8780. 9
In di catio n b iop s y -0. 540±0. 159 <0.001 0.58 3 0.42 6-0.7 97 Past TCMR -0. 356±0. 161 0.027 0.70 1 0.51 1-0.9 60
t score -2. 636±0. 129 <0.001 0.07 2 0.05 6-0.0 92 g s co re -0. 343±0. 161 0.033 0.70 9 0.51 7-0.9 73 ptc score -0. 712±0. 108 <0.001 0.49 1 0.39 7-0.6 07 SV40 T s core -0. 594±0. 203 0.003 0.55 2 0.37 1-0.8 22 ATN (an y) -0.356±0. 166 0.032 0.701 0.506-0.970
Table S 7a. T reatme nt of i -I NT epis odes acco rdin g to B anff i s co res. All i- INT bio psi es (n=37 4 ) were in cl ud ed. Key: a, P <0 .05; b, P<0 .01; c, P <0. 001 versus i1 .
Banff i score i1 i2 i3
Numb er of biop si es 222 112 40
An y th erap y 132 (5 9.3 %) 92 (82 .1 %) c 35 (87 .5 %) c IV met h yl pred nisol o ne 124 (5 6.1%) 91 (81 .3 %) c 33 (82 .5 %) b Lym p hoc yt e d eplet io n 17 (7. 7%) 15 (13 .4 %) c 14 (35 .0 %) b
IV IG± PEX 18 (8. 1%) 20 (17.9 %) 6 (15. 0%)
Ups caled t herap y 45 (20 .4%) 35 (31.2 %) a 12 (30 .0 %) b
Recurrent rej ection 72 (32 .6%) 41 (36.6 %) 20 (50.0 %) a Noncom pli an ce 28 (12 .6%) 25 (22 .3 %) b 12 (30 .0 %) b
Table S7b. Rela tio nships of treatment giv en, co mpli ance and subs equen t rejecti on in i-INT cas es a cco rding to Banff i s co re. Univ ari able l ogis tic regres sion o f t he effects o f (hi gh er) Banff i scores in t he p rediction of therap y us e, asso ci at ed nonco mpli ance, and su bs equen t acut e rejecti on epis od es (n =3 74, v ersus Ban ff i1).
OR 95% CI P va lue
An y th erap y 2.610 1.73 5-3.927 <0. 001 IV met h yl pred nisol o ne 2.44 9 1.66 5-3.6 02 <0. 001 Lym p ho c yt e d eplet io n 2.46 3 1.62 6-3.7 32 <0. 001
IV IG± PEX 1.603 1.047-2.452 0. 03
Ups caled t herap y 2.610 1.413-1.971 0. 041
Recurrent rej ection 1.388 1.021-1.888 <0. 001
Noncom pli an ce 1.842 1.269-2.671 <0.001
Table S 8a. Co mpl ete res olution of inf la mma tion in i -INT kidney s. S ub - an al ys is o f i- INT ki dne ys b y uni vari abl e and mul tivariable Cox regressi on (n =293 of 3 74 wit h s eq uenti al histol o gy). Clearan ce ti me to Banff i0 calculated from i nd ex-biops y.
HR 95%CI P value
Univa riab le cl inical risk factors a t tran splantati on
Recipi ent age ( years ) 1.011 1.001-1.0 20 0.0 24 Recipi ent s ex mal e 1.251 0.969-1.6 17 0.0 86
Deceased d ono r 0.970 0.729-1.2 89 0.8 32
Combined (vs kidn e y) 0.904 0.688-1.1 88 0.4 70 Pret rans pl ant DSA 1.309 0.991-1.7 29 0.0 58 HLA mism at ch (of 6 ) 0.989 0.913-1.0 71 0.7 87
Earl y pos ttransplan t risks and p rior (to biopsy ) even ts
Del a yed graft fun cti on 1.37 0 0.990-1.8 96 0.0 58 Earl y T cell rej ect io n 0.919 0.692-1.2 21 0.5 60 Earl y v as cul ar rej ect ion 1.151 0.589-2.2 48 0.6 81 Earl y antib od y rej ect ion 0.651 0.416-1.0 19 0.0 60
Prio r p uls e co rti cost eroids 0.77 6 0.60 2-1.0 00 0.0 50 Prio r antit h ym oc yt e gl obu lin 0.87 1 0.61 1-1.2 43 0.4 47
Univa riab le ri sk fa cto rs at biops y ti me
Time aft er t ranspl an t (mo ) 0.97 3 0.96 3-0.9 82 <0. 001 Lat e (>3 m ont hs ) bi o ps y 0.390 0.297-0.511 <0. 001 Earl y (<3 mon ths ) b i ops y 2.56 5 1.95 6-3.3 64 <0. 001 In di cation (vs p roto col) 1.25 0 0.97 1-1.6 09 0.0 84 Serum creatin in e (u mol/ L) 1.00 1 1.00 1-1.0 02 <0.001 DSA detect ed (M F I≥500) 0.964 0.716-1.298 0.810 Tacrolim us (vs c ycl osporine) th erap y
Table S8b.
Univa riab le his tolo gical risk fa ctors
Glom eruli (n umb er) 0.99 2 0.97 5-1.0 08 0.3 20
Banff g score 1.18 4 0.94 9-1.4 77 0.1 35
Ban ff i s co re 0.89 5 0.73 9-1.0 84 0.2 56 Ban ff t s co re 0.91 2 0.77 0-1.0 80 0.2 85 Ban ff v score 1.73 0 1.25 6-2.3 82 <0. 001
Ban ff pt c s core 1.014 0.881-1.167 0.849
Ban ff ci s co re 0.685 0.593-0.790 <0. 001 Ban ff ct s co re 0.67 9 0.58 5-0.7 87 <0. 001 Ban ff cv s co re 0.84 4 0.69 0-1.0 33 0.0 99 Ban ff cg s co re 0.48 0 0.31 3-0.7 37 <0.001
Ban ff ah s co re 0.780 0.655-0.939 0.008
Acute tu bul ar necro s is (an y) 1.450 1.120-1.878 0.005
C4d s co re 0.937 0.786-1.117 0.469
SV40 score 0.894 0.662-1.209 0.468
BKVAN (pres ent ) 0.726 0.468-1.128 0.154
Treatment-a sso cia ted univ ariabl e risk factors
An y treatm ent (all ) 1.353 1.010-1.813 0.043
Pulse IV m et h yp redn isolo ne 1.328 0.999-1.766 0.051 Lym p hoc yt e d eplet io n 1.747 1.216-2.511 0.003
IV IG±P EX 0.907 0.607-1.354 0.652
Up-s cal ed t reatm ent 0.710 0.532-0.948 0.020
Noncom pli an ce o r- 0.517 0.351-0.762 <0. 001 Compli an ce with th erap y 1.93 3 1.31 2-2.8 48 <0. 001
Table S8 c. Resolu ti on of infla mmation from i -I NT kidn ey s. Multi vari abl e Cox regres sion o f ris k facto rs for co mpl et e i -INT clearance (t o Banff i 0).
Multiva riabl e ri sk f acto rs of co mpl ete i nfla mmatory resolu tion
HR 95%CI P va lue
Earl y (≤3 mo) biopsy 2.69 4 2.003-3.623 0.005 In di catio n b iop s y 1.65 8 1.266-2.172 <0. 001 Recipi ent age ( yrs ) 1.01 4 1.004-1.024 0.005 Lym p ho c yt e d eplet io n 1.84 7 1.253-2.721 0.002 Compli an ce ( yes ) 1.58 0 1.054-2.367 0.027 Ban ff i s co re 0.96 2 0.783-1.183 0.715
Table S9 a. Con temp oran eou s predi ctors of progressi ve inters titi al fibrosis by s equen tial biop sy s a mplin g. Unadj usted uni vari abl e C ox regressi on of dev el opm ent o f m oderat e graft fibrosis (Banff ci≥2) in all available subs eq uent b iops ies (n =12 71 ).
HR 95%CI P va lue
Univa riab le ri sk fa cto rs at tran splan tation
Recipi ent age ( years ) 1.01 2 1.00 5-1.0 19 <0.001 Recipi ent s ex mal e 0.967 0814 -1.14 9 0.7 05
Deceased d ono r 1.036 0.84 1-1.2 76 0.7 43
Kidn e y-p an creas reci pient 0.366 0.29 4-0.4 55 <0. 001 Pret rans pl ant DSA 1.210 1.009-1.450 0.0 39 HLA mism at ch (of 6 ) 0.916 0.871-0.9 64 <0. 001 In d uct ion th erap y (v s nil ) 0.72 7 0.47 4-1.115 0.1 44
Earl y pos ttransplan t risks and p rio r (to biopsy) ev en ts
Del a yed graft fun cti on 1.872 1.54 1-2.2 73 <0. 001 Earl y T cell rej ect io n 1.766 0.450-2.151 <0. 001 Earl y v as cul ar rej ect ion 1.74 4 1.15 7-2.6 28 0.0 08 Earl y antib od y rej ect ion 1.86 1 1.39 0-2.4 91 <0. 001
Prio r p uls e corti cost eroids 1.51 8 1.28 2-1.7 98 <0.001 Prio r antit h ym oc yt e gl obu lin 1.851 1.504-2.2 78 <0. 001
Prio r BKVAN 1.55 0 1.07 8-2.2 28 0.0 18
Prio r vi remi a 1.51 3 1.16 6-1.9 64 0.0 02
At th e ti me of biop s y
Month s p ostt ransp lant 1.00 8 1.00 5-1.0 10 <0. 001 In di catio n (vs p roto col) 2.014 1.697-2.3 90 <0.001 Serum creatin in e (u mol/ L) 1.00 1 1.001-1.0 02 <0. 001 DSA detect ed (M F I≥500) 1.201 0.984-1.466 0.071 DSA pres ent (M FI≥2000) 1.796 1.400-2.302 <0.001
Table S9b. I mmuno suppressi ve th erapy at biops y
Tacrolim us (vs c ycl o spo rin e) th erap y
0.830 0.62 1-1.1 09 0.2 08
Tacrolim us d os e (m g/da y) 1.01 1 0.99 0-1.0 32 0.3 04 Tacrolim us l ev el (ng /ml) 0.97 6 0.95 1-1.001 0.0 62 C ycl ospo ri ne do se (mg/d a y) 0.99 9 0.99 7-1.0 01 0.453 C ycl ospo ri ne lev el (n g/ml ) 0.999 0.997-1.0 01 0.370 M ycoph en ol ate do se (g/d a y) 0.558 0.425-0.734 <0. 001 Prednis olon e dos e (g /da y) 0.97 5 0.96 2-0.9 88 <0. 001
Biopsy hi stopa tholo gy
HR 95% CI P value
Univa riab le biops y predi cto rs
Glom eruli (n umb er) 1.00 7 0.99 5-1.0 20 0.2 40
Ban ff i s co re 1.44 6 1.30 7-1.6 01 <0. 001 An y Banff i (i - INT) 1.78 1 1.48 3-2.1 40 <0.001
Banff g score 1.101 0.877-1.383 0.408
Ban ff t s co re 1.562 1.40 2-1.740 <0. 001
Ban ff v score 1.48 7 1.06 8-2.0 71 0.0 19
Ban ff ah s co re 1.61 3 1.44 4-1.8 02 <0. 001 Ban ff pt c s core 1.45 0 1.26 9-1.6 57 <0. 001 Ban ff ci s co re 2.906 2.646-3.190 <0.001 Ban ff ct s co re 2.888 2.613-3.192 <0.001 Ban ff cv s co re 1.936 1.721-2.1 78 <0. 001 Ban ff cg s co re 1.80 7 1.40 5-2.3 25 <0.001
C4d s co re 1.28 0 1.10 7-1.4 79 <0. 001
SV40 T s co re 1.767 1.381-2.262 <0. 001
Acute tubul ar necros is (an y) 1.835 1.535-2.194 <0.001
Table S9 c. Mul tiv a riabl e p redi cto rs of prog ressive in tersti tial fib rosi s (Banff ci≥2) using sequential biopsy sampling. Adj ust ed m ultiv ariable Cox regres sion o f in ci dent m od erat e graft fi bro sis (Ban ff ci≥2) in all available subs eq uent b iops ies (n =12 71 ).
Multiva riabl e mod el 1 : Hi stolog ical predi cto rs (ex clud i n g tu buliti s and IF/TA s co res, but in clu din g tim e p ostt ranspl ant , n =1 261 ).
HR 95% CI P va lue
i-INT (vs i 0) 1.409 1.14 1-1.740 <0. 001 Month s p ostt ransp lant 1.004 1.007-1.0 07 0.0 06 Acute tu bul ar necro s is (an y) 1.668 1.380-2.0 16 <0. 001 BKVAN (S V40 T) 1.52 6 1.01 9-2.2 87 0.0 40
Ban ff pt c s core 1.20 9 1.04 0-1.4 04 0.0 04 Ban ff cv s co re 1.60 5 1.41 2-1.8 25 <0. 001 Ban ff ah s co re 1.333 1.17 4-1.514 <0. 001
Multiva riabl e mod el 2 : Clini cal facto rs only (ex clud i n g tu buliti s b ut incl udin g tim e pos ttrans plant, n =12 26 ).
HR 95% CI P value
i-INT (vs i 0) 1.53 3 1.26 3-1.8 61 <0. 001 Month s p ostt ransp lant 1.00 9 1.00 6-1.0 11 <0.001 Kidn e y-p an creas reci pient 0.387 0.308-0.485 <0. 001 Del a yed graft fun cti on 1.44 1 1.17 6-1.7 66 <0. 001 Earl y T cell rej ect io n 1.420 1.154-1.749 <0.001 In di cation (vs p roto col) 1.415 1.17 5-1.7 05 <0. 001
Multiva riabl e model 3: Parsi monious model excludin g tubu litis
HR 95%CI P va lue
i-INT (vs i 0) 1.28 6 1.155-1.4 31 <0. 001 Month s p ostt ransp lant 1.01 0 1.00 7-1.0 12 <0. 001 Kidn e y-p an creas reci pient 0.396 0.315-0.497 <0. 001 Del a yed graft fun cti on 1.48 1 1.20 8-1.8 15 <0. 001
BKVAN 1.43 3 0.96 7-2.1 25 0.0 73
In di cation (vs p roto col) 1.41 3 1.17 2-1.7 03 <0.001
Final mul tiva ri able mod el 4: Pa rsi moni ous mod el in cluding tubuli tis
HR 95%CI P va lue
i-INT (vs i 0) 1.11 4 0.850-1.4 61 0.4 34 Ban ff t s co re 1.438 1.193-1.7 33 <0. 001 Month s p ostt ransp lant 1.00 9 1.00 7-1.0 12 <0. 001 Kidn e y-p an creas reci pient 0.380 0.303-0.477 <0. 001 Del a yed graft fun cti on 1.46 0 1.19 1-1.7 89 <0. 001 In di cation (vs p roto col) 1.37 6 1.14 1-1.6 58 <0.001 In t eractio n Ban ff i*t 0.998 0.911-1.093 0.963
Table S1 0a. Subs et-anal ysis of i -I NT biopsies and incid ent fib ros is with trea tmen t effects i ncluded . All ant eceden t, cont empo ran eo us clin ical and pat holo gical ris k facto rs and treatm ent-relat ed effects were inclu ded in univ ariabl e and m ultivari abl e m od els of m od erat e fibros i s (Ban ff ci≥2, n=2 93/ 374 bio psi es ) usin g Cox regressi on .
HR 95% CI P va lue
Univa riab le ri sk fa cto rs at tran splan tation
Recipi ent age ( years ) 0.997 0.986-1.0 09 0.670 Recipi ent s ex mal e 0.930 0.681-1.270 0.648
Deceased d ono r 0.755 0.530-1.059 0.103
Kidn e y-p an creas reci pient 0.398 0.269-0.589 <0. 001 Pret rans pl ant DSA 0.97 2 0.69 1-1.3 69 0.8 71 HLA mism at ch (of 6 ) 0.81 7 0.74 5-0.8 96 <0. 001 Induct ion th erap y (v s nil ) 0.650 0.31 9-1.3 27 0.2 37
Earl y pos ttransplan t risks and p rio r events
Del a yed graft fun cti on 1.11 9 0.76 6-1.6 33 0.5 61 Earl y T cell rej ect ion 1.55 9 1.13 5-2.1 41 0.0 06 Earl y v as cul ar rej ect ion 1.39 1 0.65 1-2.9 75 0.3 94 Earl y antib od y rej ect ion 1.66 2 1.06 5-2.5 94 0.0 25 Prio r p uls e corti cost eroids 1.66 5 1.21 7-2.2 78 <0.001 Prio r antit h ym oc yt e gl obu lin 1.602 1.086-2.365 0.018
Prio r BKVAN 1.394 0.843-2.307 0.1 95
Prio r vi remi a 1.330 0.991-2.009 0.175
At th e ti me of biop s y
Month s p ostt ransp lant 1.009 1.005-1.012 <0. 001 In di catio n (vs p roto col) 1.78 4 1.30 3-2.4 43 <0. 001 Serum creatin in e (u mol/ L) 1.00 0 0.999-1.001 0.532 DSA detect ed (M F I≥500) 1.478 1.033-2.115 0.033 DSA pres ent (M FI≥2000) 1.659 1.141-2.412 0.008
Table S10b. Uni va ri able b iopsy predi ctors
Glom eruli (n umb er) 1.00 3 0.98 2-1.024 0.7 82
Ban ff i s co re 1.34 5 1.08 1-1.6 72 0.0 08
Banff g score 0.80 4 0.57 6-1.1 22 0.1 99
Ban ff t s co re 1.35 7 1.09 9-1.675 0.0 05
Ban ff v score 1.10 0 0.72 8-1.6 60 0.6 51
Ban ff ah s co re 1.35 8 1.11 1-1.6 59 0.0 03 Ban ff pt c s core 1.15 3 0.96 8-1.3 73 0.1 12
Ban ff ci s co re 2.51 6 2.11 5-2.9 92 <0. 001 Ban ff ct s co re 2.35 2 1.97 9-2.8 02 <0. 001 Ban ff cv s co re 1.457 1.177-2.805 <0. 001 Ban ff cg s co re 1.42 7 1.01 3-2.0 10 0.0 42
C4d s co re 1.10 0 0.88 6-1.3 66 0.3 38
SV40 T s core 1.33 8 0.99 6-1.7 99 0.0 53
Acute tu bul ar n ecro s is (an y) 1.22 9 0.89 7-1.6 82 0.1 99 ANY INF (v s NIL) ND (all were i nflam ed)
Univa riab le trea tment fa ctors af ter bi opsy Post h oc effect s
HR 95% CI P va lue
An y treatm ent (all ) 1.122 0.785-1.604 0.527 Pulse m eth yp red niso lne 1.040 0.738-1.467 0.821 Lym p ho c yt e d eplet io n 1.415 0.951-2.105 0.0 87
IV IG/P EX 1.728 1.145-2.609 0.009
Ups caled t reat ment 1.230 0.877-1.724 0.231
Univa riab le adh erence to trea tmen t at biopsy ti me
Noncom pli an ce 1.737 1.195-2.527 0.004
Table S10c. Mul tiva riabl e mod el : Sensi tivit y anal ysi s clinical an d pat holo gical ri sk facto rs p redi cti ng mod erat e IF/TA (Ban ff ci≥2) by multivariabl e C ox regres sion i n i - INT su bs et wit h fol lo w-up p atho log y (n=29 3/374) and t reatment in form atio n . No effect of t reatment could be dem onst rated on lim itin g p ro gressi ve fibrosi s, and was thus not in clud ed i n the fi nal mult iv ari ab le m od el.
Co mb ined mul tiv ari able mod el of mod erate in ciden t fib rosi s
HR 95% CI P va lue
Month s p ostt ransp lant 1.00 8 1.00 4-1.0 12 <0. 001 Kidn e y-p an creas reci pient 0.447 0.295-0.678 <0. 001 In di catio n (vs p roto col) 1.29 4 0.92 1-1.8 18 0.1 73
Ban ff i s co re 0.94 2 0.71 5-1.2 41 0.6 70
Ban ff t s core 1.44 0 1.11 9-1.8 53 0.0 05
SV40 T s core 1.30 9 0.96 6-1.7 55 0.0 83
DSA pres en t (M FI≥2000) 1.50 5 1.02 2-2.2 16 0.0 38
Table S11. In cid ent fibro sis in ea rly transpl antati on: Su bset an alys is of effects of is chemi a-rep erfusion in ju ry and i-INT . M ultiv ariable Cox regres sion of d evel o pment o f mod erat e graft fib rosi s (Banff ci≥2) in samples obt ain ed withi n on e month p ostt rans plant (n =6 18 ), con fi rm ed b y additi onal strati fied Cox regres sion b y th e pres ence of i - INT (lo wer panel).
Multiva riabl e Co x reg ression model 1
HR 95% CI P va lue
Kidn e y-p an creas reci pient1 0.43 5 0.28 5-0.6 64 <0. 001
Deceased d ono r 1.574 1.063-2.330 0.0 23
Del a yed graft fun cti on2 1.71 2 1.25 0-2.3 44 <0. 001 Th ym o globuli n in du ctio n (vs b asilix um ab)3
1.42 0 1.09 0-1.8 49 0.0 09 i-INT (vs i 0) 0.81 6 0.56 4-1.1 80 0.2 80
Multiva riabl e stra ti fied Cox regressi on mod el 2 Strata=p resen ce of i -INT
HR 95%CI P va lue
Kidn e y-pan creas reci pient1 0.44 4 0.29 1-0.6 78 <0. 001
Deceased d ono r 1.580 1.067-2.340 0.0 22
Del a yed graft fun cti on2 1.69 4 1.22 3-2.3 24 <0. 001 Th ym o globuli n in du ctio n (vs b asilix um ab/nil )3
1.42 3 1.09 2-1.8 53 0.0 09
Comments: 1. Protectiv e effect of Ki dney-p an creas recipi en t was d ue to optim al don ors (aged below 50 years ); 2. The d el a yed graft fu ncti on
(req uirin g di al ys is) risk fact or was int erchangeable wit h histo lo gi cal acute tubul ar n ecrosis (dat a n ot s ho wn ). 3. Th ymoglobuli n in du ction was us ed for re-graft ed recip ients or hi gh immunol o gi cal ris k p ati ent s.
Table S1 2. Clini ca l and pa thol ogi cal ri sk fa ctors for prog ressi ve fib rosi s:
BKVAN subs et anal ysis. Th e d ev elopm ent of i nci dent m od erat e graft fi brosis (Banff ci≥2) from sequential histopathology was evaluated in biopsies with cu rren t and p ri or BKVAN (n =1 30) us in g multi vari abl e Cox regres sion and strati fied Cox regres sion: to det ermin e et iologi cal risk facto rs and ass ess t he infl uence of con cu rrent i- INT (Ban ff i≥1).
Multiva riabl e Co x reg ression : Final pa rsi moni ous mod el 1
HR 95% CI P va lue
i-INT (vs i 0) 0.92 2 0.46 5-1.8 27 0.8 15
SV40T s co re 1.44 1 0.96 8-2.1 45 0.0 72
Acute tu bul ar necro s is (an y) 2.32 0 1.20 4-4.468 0.0 12 Earl y T cell rej ect io n 2.54 1 1.55 5-5.5 90 0.0 20 In di catio n (vs p roto col) 1.82 8 1.00 7-3.3 19 0.0 47
Mod el 2: Confi rmatory mul ti variabl e s tratified Co x regress ion Strata=p resen ce of i -INT
HR 95% CI P va lue
SV40 T s core 1.543 1.03 5-2.3 01 0.0 33
Acute tu bul ar necro s is (an y) 2.426 1.25 9-4.676 0.0 08 Earl y T cell rej ect io n 2.885 1.31 1-6.3 52 0.0 08
Table S13 a. Univ ariable a ctu arial anal ysis of th e effects o f infla mmation on death -cen so red graf t su rvi val . C ox regressi on o f graft s urvival in redu ced d at as et (wit hout repeat ed sam pl es in cl uded, fi rst bi o ps y o nl y, n=577 uniqu e kid ne ys ).
HR 95%CI P va lue
Acu te his tol ogi cal risk facto r
Ban ff i≥1 2.69 5 1.30 9-5.5 50 0.0 07 Ban ff g≥1 3.60 6 1.47 4-8.8 24 0.0 05 Ban ff pt c≥1 3.72 5 1.77 2-7.8 29 0.0 01 Ban ff g+pt c≥2 5.63 5 2.63 6-12. 048 <0. 001 Ban ff C4d≥1 2.39 9 1.02 7-5.6 04 0.0 43
Chronic his tolo gi ca l ma rk ers
Ban ff ci≥1 3.61 9 1.61 0-8.134 0.0 02 Ban ff ci≥2 4.07 7 1.96 2-8.4 72 <0. 001 Ban ff ct≥1 3.04 0 1.30 3-7.0 90 0.0 10 Ban ff cg≥1 8.65 2 3.84 0-19. 497 <0. 001 Ban ff cv≥1 3.16 8 1.526-6.577 0.0 02 SV40 T d et ected 5.01 8 1.52 0-16. 568 0.0 08
Serolo gy
DSA pres en t 3.24 8 1.33 6-7.9 00 0.0 09 DSA (≥2000MFI) 4.128 1.83 4-9.2 95 0.0 01
Table S13b . Mul ti variabl e mod el of i-INT on d eath-cen so red g raft survi val . C ox regressi on o f graft survival agai nst i -IN T, adju sted for histol o gi cal risk fact ors and t he p resence of ci rcul atin g DS A (n=5 77 kid ne ys ).
Mod el 1. Full y adj usted mo del in cludi n g tim e p ostt rans plantati on (“forced in”) with cov ari at e adjustm ent for mis sing dat a (i. e. DSA M F I≥500 at biopsy).
Risk fa cto rs HR 95% CI P va lue
An y i- INT (i≥1) 4.80 4 1.58 5-14. 557 0.0 06 An y Banff cg≥1 2.84 9 0.98 9-8.2 12 0.0 53 An y Banff cv≥1 1.88 1 0.86 7-4.0 81 0.1 10 An y MV I (g+p tc≥2) 2.68 7 1.12 0-6.4 47 0.0 27 Ban ff ci (score) 2.18 6 1.32 6-3.6 02 0.0 02 Correcti on i * ci 0.62 3 0.42 4-0.9 16 0.0 16 Posttran spl ant mo nth s 1.00 3 0.99 5-1.0 11 0.4 33 An y DS A d et ected 2.83 8 1.14 4-7.0 40 0.0 24
Intermedia te model 2. Tim e p ostt ranspl ant ot her n onsi gni ficant risk fact ors were ex clud ed , as was and i ndi cation bi ops y s tat us. C ov ariate adju stm ent fo r missin g d at a was no t req uired (DS A was excl ud ed from th e final model , but predi ct ed b y oth er remaini n g “anti bod y” mark ers as M V I and Ban ff cg).
Risk fa cto rs HR 95%CI P va lue
An y i- INT (Ban ff i≥1) 4.448 1.476-13.407 0.008 An y Banff cg≥1 4.04 2 1.546-10.568 0.004 An y MV I (g+p tc≥2) 2.91 2 1.254-6.7654 0.0 13 Ban ff ci (score) 2.59 8 1.644-4.104 <0. 001 Correcti on i * ci 0.61 2 0.422-0.889 0.0 10
Fo otno tes: C I, con fidence int erval; HR , h azard rati o. MV I, mi crov as cul ar infl amm atio n; i- IN T is i nterst itial i nfl amm ation. Correction i *ci i s a co rrectio n fact or to adjust for collineari t y between Banff ci and i s cores.
Final Model 3. Fu ll y-adju st ed p arsim oni ous m odel. Tim e po sttrans pl ant an d oth er no nsi gnificant risk facto rs were ex clu ded, and covari at e adj ustm ent for missin g d at a was no t req uired (DS A was excl ud ed from the final mo del , but predi ct ed b y oth er remaini n g “anti bod y” mark ers as M V I and Banff cg).
Risk fa cto rs HR 95% CI P va lue
i-INT (i≥1) 3.82 8 1.237-11.848 0.0 20
Banff cg≥1 3.95 7 1.487-10.534 0.0 06
MVI (g+ptc≥2) 2.32 2 0.990-5.499 0.0 53
Ban ff ci s co re 2.57 0 1.618-4.082 <0. 001
Indi cation b iop s y 2.540 1.177-5.479 0.0 17 Correcti on i * ci 0.63 7 0.440-0.924 0.0 17
Footno tes: C I, con fidence int erval; HR , hazard rati o. MV I, mi crov as cul ar infl amm atio n; i- IN T is i nterst itial i nfl amm ation. Co rrectio n i *ci i s a co rrectio n fact or to adjust for collin eari t y between Ban ff ci an d i s co res.
Table S 14. Thresh old resul ts of i-INT by ou tco me anal ysis of incid en t mod erate fib ros is a nd to tal cu mulati ve graft fa ilure. All eval uable bi opsi es (n =12 73 ) with an d without i- INT (i.e. Banff i0 ) were ev alu at ed b y uni vari abl e and multi vari abl e Cox regress ion fo r inci dent fibro sis (Banff ci≥2) and cum ulat iv e graft fail ure (censo red for death). Tim e-to -event calculated from the ind ex bi ops y (ill ustrat ed Fi gure 7).
Unadju sted uni va ri able Co x reg ression mod els For moderate graft fibrosis
OR 95% CI P va lue
Ban ff i0 1.00 0
Ban ff i1 1.54 7 1.22 9-1.946 <0. 001 Ban ff i2 1.90 7 1.42 2-2.558 <0. 001 Ban ff i3 3.27 5 2.14 6-4.997 <0. 001
For death cens ored graf t failu re Ban ff i0 1.00 0
Ban ff i1 2.76 0 1.69 7-4.489 <0. 001 Ban ff i2 2.48 3 1.26 6-4.869 0. 008 Ban ff i3 4.11 3 1.64 7-10.27 0. 002
Adjus ted* uni va ria ble Cox regress ion mod els For moderate graft fibrosis
OR 95% CI P value
Ban ff i0 1.00 0
Ban ff i1 1.54 8 1.22 6-1.954 <0. 001 Ban ff i2 1.41 6 1.04 1-1.927 0. 027 Ban ff i3 2.38 7 1.55 8-3.659 <0. 001
Death cens ored graft failu re Banff i0 1.000
Banff i1 2.698 1.649-4.416 <0. 001
Figu re S1. La ck of effect of in ters ti ti al inflamma ti on on tubular in ju ry fro m i sch emia -rep erfusion in jury. Three s ensi tivit y an al yses o f in cident mod erat e chroni c fi b rosi s cat egor y (Banff ci 2) demo nst rate t he l ack of effect of co-ex istent i - INT in early (≤3mo posttransplantation) with either ATN (n=31 5, left p an el); dela yed graft funct ion requi rin g dial ys is (DGF, n=214 samp les), o r b oth his tologi cal ATN o r from DGF ki dn e ys (n=1 13).
