SDC, THE HISTOLOGY OF KIDNEY TRANSPLANT FAILURE: A LONG-TERM FOLLOW-UP STUDY
Maarten Naesens, MD PhD; Dirk RJ Kuypers, MD PhD; Katrien De Vusser, MD; Pieter Evenepoel, MD PhD; Kathleen Claes, MD PhD; Bert Bammens, MD PhD; Björn Meijers, MD PhD; Ben Sprangers, MD, PhD; Jacques Pirenne, MD PhD; Diethard Monbaliu, MD PhD; Ina Jochmans, MD PhD; Evelyne Lerut, MD PhD
SDC TABLE S1. Patient demographics of all 1197 kidney transplants, and histological appearance of all 1365 post-transplant renal allograft biopsies included in this study.
SDC TABLE S2. Prevalence of histological diagnoses over time after transplantation in all 1365 renal allograft biopsies included in this study.
SDC TABLE S3. Cox proportional hazards analysis of post-biopsy death-censored graft survival, according to individual histological parameters in the last biopsy (N=341), in univariate and multivariate (backward selection) analysis.
SDC Table S4. Clinical determinants of extensive scarring in last biopsies performed after the first post-transplant year (N=341).
SDC Table S1. Patient demographics of all 1197 kidney transplants, and histological appearance of all 1365 post-transplant renal allograft biopsies included in this study. ^ Renal diseases with recurrence potential were primary FSGS, idiopathic membranous nephropathy, IgA nephropathy, membranoproliferative glomerulopathy, nephropathy associated with systemic lupus erythematosis, ANCA-associated vasculitis, anti-GBM disease, Henoch-Schönlein purpura nephropathy, hemolytic uremic syndrome, amyloidosis, monoclonal immunoglobulin deposition disease and primary glomerulonephritis without clear diagnosis. ^ A “normal” biopsy was defined as a biopsy without any specific diagnosis (TCMR, changes suggestive of acute ABMR, PVAN, transplant glomerulopathy, glomerular pathology), and without interstitial fibrosis/tubular atrophy. Other lesions (e.g. glomerulosclerosis, arteriolar hyalinosis) could be present in these “normal” biopsies. @Different diagnoses were sometimes diagnosed simultaneously within a single biopsy. *CNI=calcineurin inhibitor
PATIENT DEMOGRAPHICS
All patients At least 1 post- transplant biopsy
No post- transplant biopsy
p-value
Number 1197 738 459
Donor age 38.8 ± 15.6 39.6 ± 15.6 37.6 ± 15.5 0.03
Donor gender (male) 747 (62.4%) 457 (61.9%) 290 (63.2%) 0.66
Deceased donor 1186 (99.1%) 730 (98.9%) 456 (99.4%) 0.45
Stroke as cause of death 502 (41.9%) 330 (44.7%) 172 (37.5%) 0.02
Recipient age 49.1 ± 13.3 47.3 ± 13.4 52.1 ± 12.6 <0.0001
Recipient gender (male) 698 (58.3%) 405 (54.9%) 293 (63.8%) 0.002
Recurrence potential of primary renal disease^ 390 (32.6%) 261 (35.5%) 129 (28.1%) 0.009
Caucasian race/ethnicity 1149 (96.0%) 704 (95.5%) 445 (97.0%) 0.18
Repeat transplantation 148 (12.4%) 101 (13.7%) 47 (10.2%) 0.08
Highest PRA% pre-transplantation 7.47 ± 19.9 8.90 ± 21.6 5.18 ± 16.5 0.002
Number of HLA mismatches 2.57 ± 1.30 2.68 ± 1.27 2.39 ± 1.32 0.0001
SDC Table S1. (continued)
5-year overall graft survival 78.4% 76.4% 81.7% 0.0359
10-year overall graft survival 59.9% 56.8% 64.9% 0.0053
5-year death-censored graft survival 86.2% 82.6% 92.4% 0.0001
10-year death-censored graft survival 74.8% 68.0% 87.1% 0.0001
RENAL ALLOGRAFT HISTOLOGY (N=1365 post-transplant biopsies)
HISTOLOGICAL DIAGNOSIS (N=1365) Prevalence (% of total number of biopsies)@
Normal biopsy^ 216 (15.8%)
Borderline changes 229 (16.8%)
Acute TCMR 479 (35.1%)
Acute ABMR 209 (15.3%)
Transplant glomerulopathy 107 (7.84%)
PVAN 24 (1.76%)
De novo or recurrent glomerular disease 84 (6.15%) Interstitial fibrosis/tubular atrophy grade 2-3 180 (13.2%)
INDIVIDUAL HISTOLOGICAL LESION SCORE (N=1365) 0 1 2 3
Banff interstitial inflammation grade 655 (48.0%) 206 (15.1%) 171 (12.5%) 333 (24.4%)
Banff tubulitis grade 697 (51.1%) 373 (27.3%) 193 (14.1%) 102 (7.47%)
Banff intimal arteritis grade 1031 (76.1%) 288 (21.3%) 32 (2.36%) 4 (0.30%)
Banff peritubular capillaritis grade 1133 (83.0%) 187 (13.8%) 31 (2.29%) 0 (0.00%)
Banff glomerulitis grade 926 (68.0%) 205 (15.1%) 160 (11.8%) 70 (5.14%)
Banff C4d deposition in peritubular capillaries 842 (65.7%) 94 (7.33%) 75 (5.85%) 271 (21.1%)
Total i score grade 445 (33.0%) 268 (19.9%) 220 (16.3%) 417 (30.9%)
Banff mesangial matrix increase 1064 (78.1%) 110 (8.07%) 138 (10.1%) 51 (3.74%)
Banff interstitial fibrosis/tubular atrophy grade 806 (59.1%) 379 (27.8%) 126 (9.23%) 54 (3.96%) Banff transplant glomerulopathy score 1254 (92.1%) 47 (3.45%) 29 (2.13%) 31 (2.28%)
Banff arteriolar hyalinosis 682 (50.0%) 365 (26.8%) 258 (18.9%) 59 (4.33%)
SDC Table S2. Prevalence of histological diagnoses over time after transplantation in all 1365 renal allograft biopsies included in this study. ^A
“normal” biopsy was defined as a biopsy without any specific diagnosis (TCMR, changes suggestive of acute ABMR, PVAN, transplant glomerulopathy, glomerular pathology), and without interstitial fibrosis/tubular atrophy. Other lesions (e.g. glomerulosclerosis, arteriolar hyalinosis) could be present in these “normal” biopsies. Of all 1365 biopsies, 294 (22%) had multiple diagnoses, in all possible combinations.
HISTOLOGICAL DIAGNOSES First year 1-5 years 5-10 years > 10 years
Number of biopsies within time frame 913 247 134 71
Normal biopsy^ 166 (18.2%) 26 (10.5%) 16 (11.9%) 8 (11.3%)
Borderline changes 171 (18.7 %) 33 (13.4 %) 17 (12.7 %) 8 (11.3 %)
Acute TCMR 398 (43.6 %) 49 (19.8 %) 25 (18.7 %) 7 (9.9 %)
Acute ABMR 165 (18.1 %) 25 (10.1 %) 8 (6.0 %) 11 (15.5 %)
Transplant glomerulopathy 12 (1.3 %) 33 (13.4 %) 32 (23.9 %) 30 (42.3 %)
PVAN 6 (0.7 %) 15 (6.1 %) 2 (1.5 %) 1 (1.4 %)
De novo or recurrent glomerular disease 22 (2.4 %) 28 (11.3 %) 18 (13.4 %) 16 (22.5 %) Interstitial fibrosis/tubular atrophy grade >1 24 (2.6%) 89 (36%) 42 (31%) 25 (35%)
SDC TABLE S3. Cox proportional hazards analysis of post-biopsy death-censored graft survival, according to individual histological parameters in the last biopsy after 1 year (N=341), in univariate and multivariate (backward selection) analysis. All hazard ratios were adjusted for age of donors and recipients transplant year, type of immunosuppression and time after transplantation of the biopsy. Parameters that were (borderline) significant in univariate analysis, but that were not retained in the final model after backward elimination, were tubulitis, intimal arteritis, glomerulitis, peritubular capillaritis, total i score, C4d deposition in glomerular capillaries, vascular intimal thickening, mesangial matrix increase and glomerulosclerosis.
Banff scores of the individual histological lesions
Number of patients
Hazard ratio in univariate analysis (95% CI)
p-value in univariate
analysis
Hazard ratio in multivariate analysis (95% CI)
p-value in
multivariate analysis Tubulitis
0 248 1.00 -- -- --
1 57 2.15 (1.43-3.23) 0.0003 -- --
2-3 36 2.64 (1.62-4.31) 0.0001 -- --
Interstitial inflammation
0 240 1.00 -- 1.00 --
1 37 1.77 (1.08-2.90) 0.0234 1.64 (0.97-2.75) 0.06
2-3 64 3.09 (2.08-4.59) <0.0001 3.40 (2.16-5.34) <0.0001
Intimal arteritis
Absent 304 1.00 -- -- --
Present 35 3.60 (2.28-5.68) <0.0001 -- --
Glomerulitis
0 252 1.00 -- -- --
1 51 1.85 (1.18-2.92) 0.0075 -- --
2-3 36 2.60 (1.61-4.19) <0.0001 -- --
Present 37 3.49 (2.28-5.35) <0.0001 -- -- Total i score
0 134 1.00 -- -- --
1 79 1.94 (1.19-3.17) 0.008 -- --
2 49 3.66 (2.15-6.23) <0.0001 -- --
3 77 4.63 (2.90-7.37) <0.0001 -- --
C4d deposition in peritubular capillaries
0-1 279 1.00 -- 1.00 --
2-3 40 2.93 (1.85-4.63) <0.0001 2.44 (1.47-4.03) 0.0005
C4d deposition in glomerular capillaries
0-1 222 1.00 -- -- --
2-3 73 1.78 (1.16-2.71) 0.008 -- --
IF/TA grade
0 92 1.00 -- 1.00 --
1 123 0.99 (0.60-1.62) 0.95 1.50 (0.83-2.71) 0.18
2 84 1.86 (1.11-3.12) 0.02 3.21 (1.78-5.77) 0.0001
3 42 3.93 (2.22-6.95) <0.0001 7.75 (3.95-15.2) <0.0001
Transplant glomerulopathy
Absent 262 1.00 -- 1.00 --
Present 77 2.06 (1.38-3.09) 0.0005 2.19 (1.38-3.47) 0.0008
Arteriolar hyalinosis
0 96 1.00 -- 1.00 --
1 94 0.47 (0.30-0.73) 0.001 0.53 (0.32-0.86) 0.01
2-3 151 0.55 (0.36-0.84) 0.006 0.59 (0.38-0.92) 0.02
Vascular intimal thickening
0 190 1.00 -- -- --
1 76 1.61 (1.05-2.47) 0.03 -- --
2-3 73 2.19 (1.41-3.41) 0.0005 -- --
0 230 1.00 -- -- --
1 34 1.29 (0.72-2.28) 0.39 -- --
2 50 1.91 (1.23-2.97) 0.004 -- --
3 26 2.56 (1.48-4.43) 0.0007 -- --
Glomerulosclerosis
0 94 1.00 -- -- --
1 115 1.16 (0.74-1.81) 0.51 -- --
2 80 1.59 (0.93-2.70) 0.09 -- --
3 52 2.79 (1.56-4.99) 0.0005 -- --
De novo/recurrent glomerular disease*
Absent 295 1.00 -- 1.00 --
Present 46 1.11 (0.66-1.85) 0.69 2.14 (1.24-3.68) 0.006
SDC TABLE S4. Clinical determinants of extensive scarring in last biopsies performed after the first post-transplant year (N=341). P-values were calculated using Chi-square testing or one-way ANOVA, as appropriate.
IF/TA < 2 and glomerulosclerosis <
50% (N=146)
IF/TA 2-3 or glomerulosclerosis >
50% (N=195) P-value
Donors
Age 35.9 ±15.4 41.7 ± 14.4 0.0005
Sex (male) 96 (65.8%) 119 (61.0%) 0.37
Deceased donation 145 (99.3%) 191 (98.0%) 0.30
Stroke as cause of death 56 (38.4%) 94 (48.2%) 0.07
Recipients
Age 46.7 ± 13.2 44.1 ± 13.5 0.08
Sex (male) 86 (58.9%) 108 (55.4%) 0.52
Recurrence potential of primary renal disease 63 (43.2%) 80 (41.0%) 0.69
Caucasian race/ethnicity 138 (94.5%) 189 (96.9%) 0.27
Repeat transplantation 19 (13.0%) 28 (14.4%) 0.72
Number of HLA mismatches 2.64 ± 1.30 2.68 ± 1.28 0.74
Type of primary immunosuppression
Number of immunosuppressants in the regimen 2.90 ± 0.64 2.82 ± 0.64 0.74
Induction therapy 25 (17.1%) 27 (13.9%) 0.40
Corticosteroids 146 (100%) 195 (100%) 0.99
Calcineurin inhibitor (cyclosporine or tacrolimus) 145 (99.8%) 192 (98.5%) 0.47
Antimetabolite (azathioprine or mycophenolate) 101 (69.2%) 123 (63.1%) 0.24
Post-transplant follow-up
Delayed graft function 15 (10.8%) 35 (18.0%) 0.047
Only non-specific changes in post-transplant biopsies 40 (27.4%) 44 (22.6%) 0.31
Specific diagnosis in any post-transplant biopsy 106 (72.6%) 151 (77.4%) 0.31
Acute TCMR during follow-up 61 (41.8%) 78 (40.0%) 0.74
TCMR grade 1 21 (14.4%) 25 (12.8%) 0.68
TCMR grade 2-3 40 (27.4%) 53 (27.2%) 0.96
Changes suggestive of acute antibody-mediated rejection during follow-up
28 (19.2%) 35 (18.0%) 0.77
Transplant glomerulopathy during follow-up 27 (18.5%) 55 (28.2%) 0.04
PVAN during follow-up 10 (6.85%) 5 (2.56%) 0.06
De novo/recurrent glomerular disease during follow-up
21 (14.4%) 34 (17.4%) 0.45
