Background
Methods
Study population
Data collection
Anti-HLA immunization and DSA detection
Exposure to CNI
Post transplant delay | Cyclosporine trough level (ng/mL) | Tacrolimus trough level (ng/mL) |
---|---|---|
0–3 months | 250–350 | 10–15 |
3–6 months | 150–250 | 8–10 |
6–12 months | 125–200 | 6–8 |
> 12 months | 100–150 | 5–8 |
Statistical methods
-
\( \overline{X} \) represents the average of all available samples (in the case of tacrolimus IPV, the average of all tacrolimus trough levels measured for time period j), Xj represents an individual data point (a single tacrolimus trough level measurement) and n the number of all available data points (the total number of all available tacrolimus trough levels during period j)
-
Abs (…) denotes the absolute value function, such that the quantitative value \( abs\left( Xj-\overline{X}\right) \)is always a non-negative value. The obtained tacrolimus trough level (C0) must be corrected to the corresponding daily tacrolimus dose (C0/D)
Results
Baseline characteristics of the entire population
Total (n = 247) | Controls (n = 82) | Reduced exposure to CNI (n = 165) | p-value | |
---|---|---|---|---|
DEMOGRAPHICS
| ||||
Age (years) | 50.9 ± 14.1 | 51.1 ± 13.1 | 50.8 ± 14.6 | 0.91 |
Male (n, %) | 173 (70.0%) | 62 (75.6%) | 111 (67.3%) | 0.18 |
BMI (kg/m2) | 25.5 ± 4.8 | 26.2 ± 4.3 | 25.1 ± 4.9 | 0.026 |
COMORBIDITIES
| ||||
Hypertension (n, %) | 235 (95.1%) | 77 (93.9%) | 158 (95.8%) | 0.54 |
No smoker (n, %) | 122 (49.4%) | 44 (53.7%) | 78 (47.3%) | |
Former smoker (n, %) | 93 (37.7%) | 28 (34.1%) | 65 (39.4%) | |
Active smoker (n, %) | 32 (13.0%) | 10 (12.2%) | 22 (13.3%) | |
Stroke (n, %) | 11 (4.5%) | 5 (6.1%) | 6 (3.6%) | 0.51 |
Diabetes (n, %) | 55 (22.3%) | 20 (24.4%) | 35 (21.2%) | 0.57 |
Type 1 diabetes | 13 (23.6%) | 3 (15.0%) | 10 (28.6%) | |
Type 2 diabetes (with insulin) | 40 (72.7%) | 17 (85.0%) | 23 (65.7%) | |
Type 2 diabetes (no insulin) | 2 (3.6%) | 0 (0.0%) | 2 (5.7%) | |
History of coronary disease (n, %) | 25 (10.1%) | 9 (11.0%) | 16 (9.7%) | 0.75 |
Heart failure (n, %) | 41 (16.6%) | 17 (20.7%) | 24 (14.5%) | 0.22 |
Peripheral artery disease (n, %) | 19 (7.7%) | 4 (4.9%) | 15 (9.1%) | 0.24 |
Chronic obstructive pulmonary disease (n, %) | 8 (3.2%) | 5 (6.1%) | 3 (1.8%) | 0.12 |
Pre-transplant cancer (n, %) | 10 (4.0%) | 4 (4.9%) | 6 (3.6%) | 0.73 |
Causal nephropathy (n, %) | ||||
Other | 25 (10.1%) | 4 (4.9%) | 21 (12.7%) | 0.27 |
Chronic glomerulonephritis | 63 (25.5%) | 21 (25.6%) | 42 (25.5%) | |
Toxic | 2 (0.8%) | 1 (1.2%) | 1 (0.6%) | |
Diabetic nephropathy | 37 (15.0%) | 10 (12.2%) | 27 (16.4%) | |
Vascular nephropathy | 20 (8.1%) | 9 (11.0%) | 11 (6.7%) | |
Unknown | 37 (15.0%) | 14 (17.1%) | 23 (13.9%) | |
Polycystic disease | 45 (18.2%) | 13 (15.9%) | 32 (19.4%) | |
Nephrectomy | 2 (0.8%) | 1 (1.2%) | 1 (0.6%) | |
Malformative uropathy | 12 (4.9%) | 6 (7.3%) | 6 (3.6%) | |
Vasculitis | 4 (1.6%) | 3 (3.7%) | 1 (0.6%) | |
Dialysis prior to transplantation (n, %) | 209 (84.6%) | 73 (89.0%) | 136 (82.4%) | 0.18 |
Peritoneal dialysis | 38 (18.2%) | 15 (20.5%) | 23 (16.9%) | |
Hemodialysis | 171 (81.8%) | 58 (79.5%) | 113 (83.1%) | |
Pre-transplant dialysis time (years) | 2.1 ± 2.0 | 2.1 ± 2.0 | 2.2 ± 2.0 | 0.73 |
TRANSPLANTATION DATA
| ||||
Viral status CMV donor/recipient (n, %) | 0.51 | |||
D−/R- | 59 (23.9%) | 22 (26.8%) | 37 (22.4%) | |
D−/R+ | 57 (23.1%) | 18 (22.0%) | 39 (23.6%) | |
D+/R- | 64 (25.9%) | 17 (20.7%) | 47 (28.5%) | |
D+/R+ | 67 (27.1%) | 25 (30.5%) | 42 (25.5%) | |
Donor type (n, %) |
0.0008
| |||
Expanded criteria donor | 63 (25.5%) | 17 (20.7%) | 46 (27.9%) | |
Standard criteria donor | 116 (47.0%) | 52 (63.4%) | 64 (38.8%) | |
Living donor | 68 (27.5%) | 13 (15.9%) | 55 (33.3%) | |
Cold ischemia time (hours) | 13.1 ± 8.9 | 14.5 ± 8.0 | 12.4 ± 9.3 |
0.023
|
HLA A-B-DR-DQ incompatibilities (n, %) | ||||
0–3 | 61 (24.7%) | 17 (20.7%) | 44 (26.7%) |
0.048
|
4–5 | 91 (36.8%) | 39 (47.6%) | 52 (31.5%) | |
6–8 | 95 (38.5%) | 26 (31.7%) | 69 (41.8%) | |
Induction treatment (n, %) | 235 (95.1%) | 77 (93.9%) | 158 (95.8%) | 0.54 |
Lymphocyte-depletive agent | 165 (70.2%) | 56 (72.7%) | 109 (69.0%) | |
Anti-interleukin-2 receptor antibodies | 70 (29.8%) | 21 (27.3%) | 49 (31.0%) | |
Mycofenolic acid cessation during follow-up | 28 (11.3%) | 9 (11.0%) | 19 (11.5%) | 0.90 |
POST-TRANSPLANTATION EVENTS
| ||||
Delayed graft function (n, %) | 72 (29.1%) | 30 (36.6%) | 42 (25.5%) | 0.070 |
Rejection (n, %) | 42 (17.0%) | 9 (11.0%) | 33 (20.0%) | 0.075 |
T cell mediated rejection | 40 (16.2%) | 8 (9.8%) | 32 (19.4%) | |
Antibody mediated rejection | 3 (1.2%) | 1 (1.2%) | 2 (1.2%) | |
Time to first rejection (years) | 0.5 ± 1.0 | 0.9 ± 1.2 | 0.4 ± 0.9 | |
Post-transplant cancer (n, %) | 29 (11.7%) | 9 (11.0%) | 20 (12.1%) | 0.79 |
Skin cancer | 11 (37.9%) | 2 (22.2%) | 9 (45.0%) | |
Hemopathy | 3 (10.3%) | 1 (11.1%) | 2 (10.0%) | |
Solid cancer | 15 (51.7%) | 6 (66.7%) | 9 (45.0%) | |
Time to post-transplant cancer (years) | 3.2 ± 1.9 | 4.0 ± 2.0 | 2.9 ± 1.8 | 0.15 |
Return in dialysis (n, %) | 18 (7.3%) | 3 (3.7%) | 15 (9.1%) | 0.12 |
Death with a functioning graft (n, %) | 22 (8.9%) | 9 (11.0%) | 13 (7.9%) | 0.42 |
Graft failure from any cause including death (n, %) | 40 (16.2%) | 12 (14.6%) | 28 (17.0%) | 0.64 |
CNI Mean Absolute Deviation (%) | ||||
Continuous | 19.9 ± 9.6 | 19.2 ± 10.3 | 20.3 ± 9.3 | 0.21 |
< 5% | 6 (2.4%) | 2 (2.4%) | 4 (2.4%) | 1.00 |
< 15% | 87 (35.2%) | 36 (43.9%) | 51 (30.9%) |
0.044
|
> 30% | 32 (13.0%) | 12 (14.6%) | 20 (12.1%) | 0.58 |
> 50% | 2 (0.8%) | 1 (1.2%) | 1 (0.6%) | 1.00 |
Baseline characteristics of patients according to “exposure to CNI” status
Follow-up data: DSA detection and impact of reduced exposure to CNI on DSA appearance
Population (n = 247) | No DSA (n = 208) | De novo DSA (n = 39) | p-value | |
---|---|---|---|---|
DEMOGRAPHICS
| ||||
Age (years) | 50.9 ± 14.1 | 51.7 ± 14.0 | 46.6 ± 13.8 |
0.039
|
Male (n, %) | 173 (70.0%) | 142 (68.3%) | 31 (79.5%) | 0.16 |
BMI (kg/m2) | 25.5 ± 4.8 | 25.3 ± 4.9 | 26.4 ± 4.1 | 0.16 |
COMORBIDITIES
| ||||
No smoker (n, %) | 122 (49.4%) | 101 (48.6%) | 21 (53.8%) | 0.81 |
Former smoker (n, %) | 93 (37.7%) | 80 (38.5%) | 13 (33.3%) | |
Current smoker (n, %) | 32 (13.0%) | 27 (13.0%) | 5 (12.8%) | |
Stroke (n, %) | 11 (4.5%) | 11 (5.3%) | 0 (0.0%) | 0.22 |
Diabetes (n, %) | 55 (22.3%) | 44 (21.2%) | 11 (28.2%) | 0.33 |
Type 1 diabetes | 13 (23.6%) | 9 (20.5%) | 4 (36.4%) | |
Type 2 diabetes (with insulin) | 40 (72.7%) | 34 (77.3%) | 6 (54.5%) | |
Type 2 diabetes (no insulin) | 2 (3.6%) | 1 (2.3%) | 1 (9.1%) | |
History of coronary disease (n, %) | 25 (10.1%) | 21 (10.1%) | 4 (10.3%) | 1.00 |
Heart failure (n, %) | 41 (16.6%) | 33 (15.9%) | 8 (20.5%) | 0.47 |
Peripheral artery disease (n, %) | 19 (7.7%) | 16 (7.7%) | 3 (7.7%) | 1.00 |
Pre-transplant cancer (n, %) | 10 (4.0%) | 9 (4.3%) | 1 (2.6%) | 1.00 |
Causal nephropathy (n, %) | 0.24 | |||
Other | 25 (10.1%) | 20 (9.6%) | 5 (12.8%) | |
Chronic glomerulonephritis | 63 (25.5%) | 52 (25.0%) | 11 (28.2%) | |
Toxic | 2 (0.8%) | 2 (1.0%) | 0 (0.0%) | |
Diabetic nephropathy | 37 (15.0%) | 27 (13.0%) | 10 (25.6%) | |
Vascular nephropathy | 20 (8.1%) | 19 (9.1%) | 1 (2.6%) | |
Unknown | 37 (15.0%) | 35 (16.8%) | 2 (5.1%) | |
Polycystic disease | 45 (18.2%) | 38 (18.3%) | 7 (17.9%) | |
Nephrectomy | 2 (0.8%) | 1 (0.5%) | 1 (2.6%) | |
Malformative uropathy | 12 (4.9%) | 10 (4.8%) | 2 (5.1%) | |
Vasculitis | 4 (1.6%) | 4 (1.9%) | 0 (0.0%) | |
Dialysis prior to transplantation (n, %) | 209 (84.6%) | 174 (83.7%) | 35 (89.7%) | 0.33 |
Peritoneal dialysis | 38 (18.2%) | 32 (18.4%) | 6 (17.1%) | |
Hemodialysis | 171 (81.8%) | 142 (81.6%) | 29 (82.9%) | |
Pre-transplant dialysis time (years) | 2.1 ± 2.0 | 2.1 ± 1.9 | 2.2 ± 2.1 | 0.78 |
TRANSPLANTATION DATA
| ||||
Viral status CMV donor/recipient (n, %) | 0.72 | |||
D−/R- | 59 (23.9%) | 47 (22.6%) | 12 (30.8%) | |
D−/R+ | 57 (23.1%) | 48 (23.1%) | 9 (23.1%) | |
D+/R- | 64 (25.9%) | 55 (26.4%) | 9 (23.1%) | |
D+/R+ | 67 (27.1%) | 58 (27.9%) | 9 (23.1%) | |
Donor type (n, %) | ||||
Expanded criteria donor | 63 (25.5%) | 55 (26.4%) | 8 (20.5%) | 0.72 |
Standard criteria donor | 116 (47.0%) | 97 (46.6%) | 19 (48.7%) | |
Living donor | 68 (27.5%) | 56 (26.9%) | 12 (30.8%) | |
Cold ischemia time (hours) | 13.1 ± 8.9 | 13.1 ± 8.5 | 12.8 ± 10.9 | 0.38 |
HLA A-B-DR-DQ incompatibilities (n, %) |
0.016
| |||
0–3 | 61 (24.7%) | 55 (26.4%) | 6 (15.4%) | |
4–5 | 91 (36.8%) | 81 (38.9%) | 10 (25.6%) | |
6–8 | 95 (38.5%) | 72 (34.6%) | 23 (59.0%) | |
Induction treatment (n, %) | 235 (95.1%) | 196 (94.2%) | 39 (100.0%) | 0.22 |
Lymphocyte-depletive agent | 165 (70.2%) | 136 (69.4%) | 29 (74.4%) | |
Anti-interleukin-2 receptor antibodies | 70 (29.8%) | 60 (30.6%) | 10 (25.6%) | |
Reduced exposure to CNI (n, %) | 165 (66.8%) | 129 (62.0%) | 36 (92.3%) |
0.0002
|
Mycophenolic acid cessation | ||||
During the entire follow-up | 28 (11.3%) | 26 (12.5%) | 2 (5.1%) | 0.27 |
Before the first detection of DSAa | 26 (10.5%) | 26 (12.5%) | 0 (0.0%) |
0.019
|
POST-TRANSPLANTATION EVENTS
| ||||
Delayed graft function (n, %) | 72 (29.1%) | 62 (29.8%) | 10 (25.6%) | 0.60 |
Rejection (n, %) | 42 (17.0%) | 30 (14.4%) | 12 (30.8%) |
0.013
|
T cell mediated rejection | 40 (16.2%) | 30 (14.4%) | 10 (25.6%) | |
Antibody mediated rejection | 3 (1.2%) | 0 (0.0%) | 3 (7.7%) | |
Time to first rejection (years) | 0.5 ± 1.0 | 0.3 ± 0.6 | 1.1 ± 1.6 | |
Post-transplant neoplasia (n, %) | 29 (11.7%) | 26 (12.5%) | 3 (7.7%) | 0.59 |
Skin cancer | 11 (37.9%) | 11 (42.3%) | 0 (0.0%) | |
Hemopathy | 3 (10.3%) | 3 (11.5%) | 0 (0.0%) | |
Solid cancer | 15 (51.7%) | 12 (46.2%) | 3 (100.0%) | |
Time to post-transplant cancer (years) | 3.2 ± 1.9 | 3.1 ± 1.9 | 4.0 ± 1.8 | 0.44 |
Return in dialysis (n, %) | 18 (7.3%) | 10 (4.8%) | 8 (20.5%) |
0.003
|
Death with a functioning graft (n, %) | 22 (8.9%) | 19 (9.1%) | 3 (7.7%) | 1.00 |
Graft failure from any cause including death (n, %) | 40 (16.2%) | 29 (13.9%) | 11 (28.2%) |
0.027
|
Mean Absolute Deviation (%) | ||||
Continuous | 19.9 ± 9.6 | 19.8 ± 9.3 | 20.7 ± 11.5 | 0.99 |
< 5% | 6 (2.4%) | 5 (2.4%) | 1 (2.6%) | 1.00 |
< 15% | 87 (35.2%) | 76 (36.5%) | 11 (28.2%) | 0.32 |
> 30% | 32 (13.0%) | 26 (12.5%) | 6 (15.4%) | 0.62 |
> 50% | 2 (0.8%) | 1 (0.5%) | 1 (2.6%) | 0.29 |
Event | Reduced exposure to CNI | Nb events/Nb patients | Univariate model | Multivariate modela | ||
---|---|---|---|---|---|---|
HR (CI 95%) | p | HR (CI 95%) | p | |||
First detection of one DSA with MFI > 1000 | No | 2/81 (2.5%) | 1.00 | 1.00 | ||
Yes | 35/166 (21.1%) | 10.43 (2.50–43.46) |
0.001
| 9.77 (2.34–40.77) |
0.002
| |
First detection of one DSA with MFI > 6000 | No | 1/82 (1.2%) | 1.00 | 1.00 | ||
Yes | 22/165 (13.3%) | 12.31 (1.66–91.47) |
0.014
| 11.54 (1.55–85.93) |
0.017
| |
First detection of one DSA with MFI > 10,000 | No | 1/84 (1.2%) | 1.00 | 1.00 | ||
Yes | 16/163 (9.8%) | 8.86 (1.17–66.92) |
0.034
| 7.40 (0.97–56.31) | 0.053 | |
First detection of DSA(s) with total MFI > 6000 | No | 1/82 (1.2%) | 1.00 | 1.00 | ||
Yes | 23/165 (13.9%) | 12.81 (1.73–94.97) |
0.013
| 12.02 (1.62–89.25) |
0.015
| |
First detection of DSA(s) with total MFI > 10,000 | No | 1/83 (1.2%) | 1.00 | 1.00 | ||
Yes | 19/164 (11.6%) | 10.75 (1.44–80.43) |
0.021
| 9.50 (1.26–71.43) |
0.029
| |
First rejection | No | 1/83 (1.2%) | 1.00 | 1.00 | ||
Yes | 11/164 (6.7%) | 5.65 (0.73–43.74) | 0.097 | 5.65 (0.73–43.74) | 0.097 | |
Post-transplant neoplasia | No | 10/88 (11.4%) | 1.00 | 1.00 | ||
Yes | 18/159 (11.3%) | 1.16 (0.53–2.52) | 0.71 | 1.20 (0.55–2.62) | 0.64 | |
Post-transplant neoplasia (excluding skin neoplasia) | No | 8/88 (9.1%) | 1.00 | 1.00 | ||
Yes | 10/159 (6.3%) | 0.75 (0.30–1.91) | 0.55 | 0.75 (0.30–1.91) | 0.55 | |
Return in dialysis | No | 3/87 (3.4%) | 1.00 | 1.00 | ||
Yes | 15/160 (9.4%) | 3.22 (0.93–11.22) | 0.066 | 3.22 (0.93–11.22) | 0.066 | |
Patient survival | No | 9/87 (10.3%) | 1.00 | 1.00 | ||
Yes | 13/160 (8.1%) | 1.01 (0.43–2.38) | 0.97 | 1.03 (0.44–2.43) | 0.94 | |
Graft survival | No | 12/87 (13.8%) | 1.00 | 1.00 | ||
Yes | 28/160 (17.5%) | 1.57 (0.80–3.11) | 0.19 | 1.64 (0.82–3.28) | 0.16 |