Electronic Supplementary Material
 Title: Potential role of post-transplant hypogammaglobulinemia in the risk of Clostridium
difficile infection after kidney transplantation: a case-control study.
 Authors´ affiliations:
Julia Origüen1, Mario Fernández-Ruiz1, Carlos Lumbreras1, María Ángeles Orellana2,
Francisco López-Medrano1, Tamara Ruiz-Merlo1, Rafael San Juan1, Ana García-Reyne1,
Esther González3, Natalia Polanco3, Estela Paz-Artal4, Amado Andrés3, José María Aguado1
1
Unit of Infectious Diseases,
2
Department of Microbiology,
3
Department of Nephrology and
4
Department of
Immunology. Hospital Universitario "12 de Octubre". Instituto de Investigación Hospital "12 de Octubre" (i+12).
School of Medicine, Universidad Complutense. Madrid, Spain.
 Corresponding author: Julia Origüen. Unit of Infectious Diseases. Hospital Universitario
"12 de Octubre". Centro de Actividades Ambulatorias, 2ª planta, bloque D. Avda. de
Córdoba, s/n. Postal code 28041. Madrid, Spain. Phone: +34 913908000 (ext. 4632). Fax:
+34 914695775. E-mail address: josabater@hotmail.com
1
Results.
Table S1. Odds ratios adjusted by various clinical variables for the development of CDI
between months 1 and 6 after transplantation in presence of IgG hypogammaglobulinemia
(serum levels <700 mg/dL) at month 1.
Two-variable modelsa
Adjustment variable
Serum albumin-adjusted
modelsb
OR
95% CI
P-value
OR
95% CI
P-value
Age-adjusted CCI
7.15
1.89 - 26.97
0.004
7.15
1.89 - 26.97
0.004
Cold ischemia time, hours
5.89
1.72 - 20.18
0.005
5.89
1.72 - 20.18
0.005
Delayed graft function
6.25
1.83 - 21.35
0.003
6.55
1.85 - 23.27
0.004
Prior CMV disease
10.62
2.18 - 51.86
0.003
10.62
2.18 - 51.86
0.003
Prior acute graft rejection
6.33
1.75 - 22.86
0.005
6.33
1.75 - 22.86
0.005
Total length of prior ß-lactam
therapy, DDD
19.99
3.09 - 129.42
0.002
19.99
3.09 - 129.42
0.002
CCI: Charlson comorbidity index; CDI: Clostridium difficile infection; CI: confidence interval; CMV:
cytomegalovirus; DDD: defined daily dose; OR: odds ratio.
a Each
model incorporates two variables: IgG HGG at month 1 and the corresponding adjustment variable.
b Each
model is further adjusted by serum albumin levels at month 1.
2
Table S2. Age-matching criterion: comparison of demographics, baseline and transplant-related
characteristics in recipients with CDI and age-matched controls.
CDI group
(n = 41)
Age-matched
control group
(n = 41)
P-value
58.5 ± 15.3
58.4 ± 14.9
0.981
22 (53.7)
22 (53.7)
1.000
4 (2-7)
4 (2-5)
0.058
Pre-transplant diabetes mellitus [n (%)]
16 (39.0)
10 (24.4)
0.154
Previous KT [n (%)]
6 (14.6)
6 (14.6)
1.000
Age of recipient, years [mean ± SD]
Male gender [n (%)]
Age-adjusted CCI [median (IQR)]
Etiology of underlying ESRD [n (%)]
0.207
Glomerulonephritis
7 (17.1)
6 (14.6)
Diabetic nephropathy
10 (24.4)
5 (12.2)
Nephroangiosclerosis
4 (9.8)
10 (24.4)
Policystosis
5 (12.2)
3 (7.3)
Other
15 (36.6)
17 (41.5)
38 (92.7)
35 (85.4)
0.482
1.9 (1.1-4.4)
1.1 (0.5-2.3)
0.017
5 (12.2)
4 (9.8)
1.000
29 (70.7)
22 (53.7)
0.111
Pre-transplant use of histamine H2-receptor
antagonists [n (%)]
0 (0.0)
4 (9.8)
0.117
CMV serostatus D+/R- [n (%)]
0 (0.0)
2 (4.9)
0.494
57.5 ± 17.1
54.9 ± 18.3
0.514
Donor after brain death
30 (73.2)
29 (70.7)
0.806
Donor after circulatory death
11 (26.8)
9 (22.0)
0.607
0 (0.0)
3 (7.3)
0.241
5 (4-5)
4 (3-5)
0.132
19.1 ± 8.5
17.8 ± 7.1
0.459
10 (24.4)
7 (17.1)
0.414
0 (0-1)
0 (0-0)
0.286
Induction therapy with ATG [n (%)]
20 (48.8)
13 (31.7)
0.115
Anti-CMV prophylaxis [n (%)]
17 (41.5)
14 (34.1)
0.494
Pre-transplant dialysis [n (%)]
Dialysis vintage, years [median (IQR)]
Pre-transplant recent
hospitalizationa
[n (%)]
Pre-transplant use of proton pump inhibitors [n (%)]
Age of donor, years [mean ± SD]
Type of donor [n (%)]
Living donor
Number of HLA mismatches [median (IQR)]
Cold ischemia time, hours [mean ± SD]
Transfusion
requirementb
[n (%)]
Number of packed red blood cells units
transfused [mean (IQR)]
ATG: antithymocyte globulin; CCI: Charlson comorbidity index, CDI: Clostridium difficile infection; CMV:
cytomegalovirus; D: donor; ESRD: end-stage renal disease; HLA: human leukocyte antigen; IQR: interquartile
range; KT: kidney transplantation; R: recipient; SD: standard deviation.
a Within
b
the 6 months before transplantation.
During the transplant procedure or within the first week.
3
Table S3. Age-matching criterion: comparison of post-transplant variables in kidney transplant
recipients with CDI and age-matched controls.a
CDI group
(n = 41)
Age-matched
control group
(n = 41)
P-value
Delayed graft function [n (%)]
30 (73.2)
20 (48.8)
0.024
Prior AR [n (%)]
10 (24.4)
3 (7.3)
0.034
Prior CMV diseaseb [n (%)]
12 (29.3)
2 (4.9)
0.003
28 (17.5-55.5)
16 (9-26.5)
0.005
36 (87.8)
36 (87.8)
1.000
1 (2.4)
3 (7.3)
0.616
Total length of hospitalization, days [median (IQR)]
Prior use of proton pump inhibitors [n (%)]
Prior use of histamine H2-receptor antagonists [n (%)]
Prior antibiotic therapy [n (%)]
Total length of therapy, DDD [mean (IQR)]
Prior use of ß-lactams [n (%)]
29 (70.7)
18 (43.9)
0.014
11 (0-26)
0 (0-7.5)
0.005
25 (61.0)
11 (26.8)
0.002
7 (0-20)
0 (0-3.5)
0.007
13 (31.7)
6 (14.6)
0.067
0 (0-3)
0 (0-0)
0.093
20 (48.8)
6 (14.6)
0.001
0 (0-8.5)
0 (0-0)
0.001
4 (9.8)
1 (2.4)
0.359
0 (0-0)
0 (0-0)
0.176
5 (12.2)
4 (9.8)
1.000
0 (0-0)
0 (0-0)
0.682
16 (39.0)
8 (19.5)
0.052
0 (0-7)
0 (0-0)
0.034
Total length of therapy, DDD [mean (IQR)]
Prior use of cephalosporins [n (%)]
Total length of therapy, DDD [mean (IQR)]
Prior use of carbapenems [n (%)]
Total length of therapy, DDD [mean (IQR)]
Prior use of piperacillin-tazobactam [n (%)]
Total length of therapy, DDD [mean (IQR)]
Prior use of other penicillins [n (%)]
Total length of therapy, DDD [mean (IQR)]
Prior use of quinolones [n (%)]
Total length of therapy, DDD [mean (IQR)]
AR: acute graft rejection; CDI: Clostridium difficile infection; CMV: cytomegalovirus; DDD: defined daily dose;
IQR: interquartile range; KT: kidney transplantation.
a Exposure
to risk factors was assessed from the date of transplantation to either the date of diagnosis of the first
episode of CDI (cases) or the analogous “pseudo-date of diagnosis” (age-adjusted controls).
b All
cases of CMV disease were further classified as viral syndrome.
4
Table S4. Age-matching criterion: multivariate analysis (logistic regression model) of risk factors
for the development of post-transplant CDI.
Multivariate analysisb
Univariate analysis
OR
95% CI
P-value
OR
95% CI
P-value
Age-adjusted CCIa
1.24
0.99 - 1.56
0.061
-
-
-
Delayed graft function
2.86
1.34 - 7.21
0.024
2.99
1.09 - 8.22
0.033
Prior CMV disease
8.07
1.67 - 38.87
0.003
7.26
1.42 - 37.21
0.017
Prior AR
4.09
1.03 - 16.16
0.034
4.03
0.91 - 17.89
0.067
Total length of prior ß-lactam
therapy, DDDa
1.04
0.99 - 1.07
0.059
-
-
-
AR: acute graft rejection; CCI: Charlson comorbidity index; CDI: Clostridium difficile infection; CI: confidence
interval; CMV: cytomegalovirus; DDD: defined daily dose; OR: odds ratio.
a Per
unitary increment.
b Hosmer-Lemeshow
test: P-value = 0.431.
5
Table S5. Age-matching criterion: comparison of immune parameters at different time points in
recipients with CDI and age-matched controls.
CDI group
Age-matched
control group
39 / 41
39 / 41
HGG of any classb [n (%)]
9 (23.1)
7 (17.9)
0.575
IgG HGG [n (%)]
5 (12.8)
2 (5.1)
0.431
IgA HGG [n (%)]
4 (10.5)
1 (2.6)
0.358
IgM HGG [n (%)]
1 (2.6)
4 (10.5)
0.358
38 / 41
37 / 41
C3 HCC [n (%)]
10 (26.3)
13 (36.1)
0.363
C4 HCC [n (%)]
1 (2.6)
2 (5.4)
0.615
CDI group
Age-marched
control group
P-value
19 / 25
28 / 41
HGG of any classb [n (%)]
15 (78.9)
17 (60.7)
0.188
IgG HGG [n (%)]
15 (78.9)
13 (46.4)
0.026
IgA HGG [n (%)]
1 (5.3)
2 (7.1)
1.000
IgM HGG [n (%)]
5 (26.3)
8 (28.6)
0.865
17 / 25
28 / 41
C3 HCC [n (%)]
5 (29.4)
5 (17.9)
0.467
C4 HCC [n (%)]
2 (12.5)
2 (7.4)
0.621
CDI group
Age-matched
control group
P-value
5 / 10
29 / 41
HGG of any classb [n (%)]
5 (100.0)
10 (34.5)
0.011
IgG HGG [n (%)]
3 (60.0)
9 (31.0)
0.319
IgA HGG [n (%)]
1 (20.0)
1 (3.4)
0.276
IgM HGG [n (%)]
1 (20.0)
3 (10.3)
0.488
5 / 10
28 / 41
C3 HCC [n (%)]
1 (20.0)
1 (3.6)
0.284
C4 HCC [n (%)]
0 (0.0)
0 (0.0)
NA
Baseline
No. at risk with measured parameter (serum
immunoglobulin levels)a / total no. at risk
No. at risk with measured parameter (serum
complement levels)a / total no. at risk
Month 1
No. at risk with measured parameter (serum
immunoglobulin levels)a / total no. at risk
No. at risk with measured parameter (serum
complement levels)a / total no. at risk
Month 6
No. at risk with measured parameter (serum
immunoglobulin levels)a / total no. at risk
No. at risk with measured parameter (serum
complement levels)a / total no. at risk
P-value
CDI: Clostridium difficile infection; HCC: hypocomplementemia ; HGG: hypogammaglobulinemia.
a Cases
at risk were those who had not developed their first episode of CDI before the corresponding date
of immune assessment, whereas all the age-matched controls were deemed at risk at each time point.
b Hypogammaglobulinemia
affecting 1 class.
6
Table S6. Age-matching criterion: multivariate analysis (Cox proportional hazards models) of
risk factors for poor outcome (graft loss and/or all-cause death).
Univariate analysis
Multivariate analysis
HR
95% CI
P-value
HR
95% CI
P-value
Age of recipienta
1.05
1.01 - 1.09
0.013
1.05
1.01 - 1.09
0.012
Prior CMV disease
1.99
0.76 - 5.18
0.159
-
-
-
Prior AR
2.17
0.79 - 5.99
0.134
-
-
-
CDI
6.73
1.97 - 23.03
0.002
6.92
2.01 - 23.74
0.002
AR: acute graft rejection; CDI: Clostridium difficile infection; CI: confidence interval; CMV:
cytomegalovirus; HR: hazard ratio.
a Per
unitary increment.
7