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Abstract
Objectives: New-onset diabetes mellitus after
transplant is a common complication in renal allograft
recipients. Recently, a high prevalence of diabetes
mellitus has been reported in patients with chronic
hepatitis C virus. The association between hepatitis C
and diabetes mellitus is well demonstrated in the
general population, but some controversy still exists.
This work aimed to study the effect of pretransplant
hepatitis C virus on the development of new-onset
diabetes mellitus after transplant in Egyptian living-
donor renal allotransplant recipients.
Materials and Methods: This retrospective single
center study included 913 kidney transplant recipients
who were transplanted at Mansoura Urology and
Nephrology Center between 2000 and 2010. The
patients were divided into 4 groups according to their
hepatitis C virus serology and diabetic status.
Results: Pretransplant dialysis duration and number
of blood transfusion units were statistically
significant among both viremic and nonviremic
groups. With respect to induction therapy, a highly
statistical significance was observed between the 4
groups regarding presence and type of adjuvant
therapy (
P
< .001). With respect to maintenance
immunosuppression, high statistically significant
results were observed regarding steroid and
rapamycin between the 4 groups (
P
< .001) with
lower significance regarding mycophenolate mofetil
(
P
= .04) but no significance regarding azathioprine,
cyclosporine, or tacrolimus therapy. Incidence of
new-onset diabetes mellitus after transplant was
statistically higher in the viremic than nonviremic
group (
P
< .001).
Conclusions: There was a positive correlation
between incidence of new-onset diabetes mellitus
after transplant and positive pretransplant hepatitis
C virus status.
Key words: Kidney, Viremic state, Immunosuppression
Introduction
With improvements in patient and graft survival after
transplant in the last decade, increasing attention has
been placed on nonimmunologic outcomes that
contribute to patient morbidity and mortality. Among
the leading causes of death in renal transplant
recipients are cardiovascular disease and infection.
New-onset of diabetes mellitus (DM) after transplant
(NODAT) has been linked to higher rates of
cardiovascular disease and infection and is a major
cause of morbidity and mortality.1The NODAT is a
common complication in renal allograft recipients.
Recently, a high prevalence of DM has been
reported in patients with chronic hepatitis C virus
(HCV) infection with or without liver cirrhosis, liver
transplant recipients, and renal transplant patients.
However, the association is controversial. Among
several factors implicated in the development of
$&
".,=
Copyright © Başkent University 2015
Printed in Turkey. All Rights Reserved.
From the 1Department of Dialysis and Transplantation, The Urology and Nephrology Center,
Mansoura University, Mansoura; and the 2Department of Nephrology, Zagazig University,
Zagazig, Egypt
Acknowledgements: The a uthors have no conflicts of interest to declare. No funding was
received for this study.
Corresponding author: Mohamed Hamed Abbas, Urology and Nephrology Center, Mansoura
University, El Gomhoria Street, P.O. Box 35516, Mansoura, Egypt
Phone: +20 50 226 2222 Fax: +20 50 226 3717 E-mail: dr_hamed_414@yahoo.com
Experimental and Clinical Transplantation (2015) 1: 26-34
Effect of Pretransplant Hepatitis C Virus on the
Development of New-Onset Diabetes Mellitus After
Transplant in Egyptian Living-Donor Renal Allotransplant
Recipients at Mansoura Urology and Nephrology Center
Mohamed H. Abbas,1Mabrouk I. Ismail,2Salem A. El Deeb,2Ayman M. Nagib,1
Nabil M. Hassan,1Ayman F. Refaie,1Hanzada M. El Maghrabi,1
Ahmed A. Denewar,1Mohamed A. Bakr1
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34
posttransplant DM are the diabetogenic effects of
immunosuppressive drugs, such as steroids and
calcineurin inhibitors, and genetic predisposition.2
Infection with HCV is 1 of the most important causes
of cirrhosis and hepatocellular carcinoma and has a
large effect on public health worldwide. The HCV is
hepatotropic and lymphotropic. Replication of HCV
in diseased extrahepatic organs and tissues may
trigger latent autoimmunity or induce autoimmune
disorders and cause liver injury.3
The association between type 2 DM and chronic
HCV infection was first reported in 1994, when it was
observed that the prevalence of type 2 DM was
significantly higher in patients with HCV-related
cirrhosis than patients with cirrhosis resulting from
other liver diseases.4
Materials and Methods
#*=2.7=<
This work was performed all patients with end-stage
renal disease who were transplanted at Mansoura
Urology and Nephrology Center from the beginning
of January 2000 to the end of December 2010. The data
of the patients were retrospectively reviewed. Patients
who were negative for hepatitis B surface antigen and
living patients with a functioning graft for ≥ 6 months
posttransplant were included in the study. Patients
were excluded from the study when they were
hepatitis B surface antigen-positive (acquired the
infection either pretransplant or posttransplant) (17
patients), died or had graft failure within the first 6
months posttransplant (22 patients), were lost to
follow-up (56 patients), had pretransplant DM (11
patients), had DM risk factors such as family history
(59 patients), and non-Egyptian renal transplant
recipients (35 patients). After excluding the patients
who had not fulfilled the inclusion criteria, 913 patients
were included. Our patients were divided into 4
groups according to their DM and HCV antibody
serologic status: group 1 patients (511 patients) were
HCV negative without posttransplant DM; group 2
patients (87 patients) were HCV negative with
posttransplant DM; group 3 patients (230 patients)
were HCV positive without posttransplant DM; and
group 4 patients (85 patients) were HCV positive with
posttransplant DM.
The study protocol was approved by the
institutional review board at The Urology and
Nephrology Center (Mansoura, Egypt), complied with
the Declaration of Helsinki and a written informed
consent was obtained from all the study participants.
#;.=;*7<95*7=.?*5>*=287
All patients were evaluated before kidney transplant.
Thorough history was taken with special emphasis on
type and duration of dialysis, number of blood
transfusions, any procedure that could lead to HCV
transmission, original kidney disease, DM symptoms
(include polyuria, polydipsia, and unexplained weight
loss), family history of DM, history of acute diabetic
complications, and thorough clinical examination with
special attention to liver and spleen examination.
#8<==;*7<95*7=.?*5>*=287
After kidney transplant, our recipients were primarily
immunosuppressed according to standardized pro-
tocols including different immunosuppressive drugs
such as steroids, tacrolimus, cyclosporine, myco-
phenolate mofetil, sirolimus, and azathioprine. Graft
function, patient survival, and graft survival were
assessed.
872=8;270/8;7.@87<.=8/-2*+.=.<6.552=><*/=.;
=;*7<95*7=
All patients had blood glucose measurements perfor-
med routinely during the initial hospitalization at
the time of transplant. Blood glucose measurements
were made every 12 hours for the first 3 days after
transplant. Thereafter, blood glucose levels were
measured daily while the recipient was an inpatient,
twice weekly for the first posttransplant month as an
outpatient, weekly for the second posttransplant
month, and whenever patients had routine chemistry
studies. The NODAT was diagnosed according to
American Diabetes Association guidelines (2011).5
Diagnostic criteria included (1) symptoms of DM plus
random plasma glucose ≥ 200 mg/dL (11.1 mmol/L),
hemoglobin A1c ≥ 6.5% (48 mmol/mol) (symptoms
included polyuria, polydipsia, and unexplained
weight loss); (2) fasting plasma glucose ≥ 126 mg/dL
(7.0 mmol/L) (fasting was defined as no caloric intake
for at least 8 hours); and (3) 2-hour plasma glucose
≥ 200 mg/dL (11.1 mmol/L) during an oral glucose
tolerance test.5
--2=287*5-*=*,855.,=.-
Additional data collected included recipient age
and sex, donor age and sex, donor and recipient
relationship, cause of end-stage renal disease, same or
27
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34 Exp Clin Transplant
28
different compatible blood group, human leukocyte
antigen (HLA) types (HLA-A, B, and DR) and number
of matches and mismatches, viral profile (hepatitis
B surface antigen and antibody, HCV antibody,
cytomegalovirus immunoglobulin M, and human
immunodeficiency virus 1 and 2 antibody), duration
of dialysis, and pretransplant blood transfusion.
%=*=2<=2,*5*7*5B<.<
The findings were recorded, tabulated, and analyzed
by (SPSS for Windows, release 10 SPSS Inc. Chicago,
III, USA, 1993). Analysis of variance was used to
compare continuous data between the 4 groups.
Categorical data were compared using chi-square test.
Graft and patient survival were computed using
Kaplan-Meier method. A value of P ≤ .05 was
considered statistically significant.
Results
.680;*912,-*=*8/=1.;.,292.7=<*7--878;<
In this cohort study, patients who developed
NODAT were significantly older in both diabetic
groups (group 2 and 4), the mean recipient age in
years at transplant procedure time was statistically
significant (P< .001); and the age interval between
&*+5. Comparison of the Groups
Pretransplant Characteristics Group 1 Group 2 Group 3 Group 4
P
≤
No: DM DM No: DM DM
HCV-Negative HCV-Negative HCV-Positive HCV-Positive
(n = 511) (n = 87) (n = 230) (n = 85)
Recipient age (y) 26.06 ± 10.4 36.5 ± 10.3 29.1 ± 10.7 36.2 ± 10.2 .001
Recipient sex (male/female) 359/152 65/22 177/53 70/15 .2
Donor age (y) 37.6 ± 10.3 33.2 ± 8.2 36.7 ± 11.02 35.7 ± 10.6 .002
Donor sex (male/female) 214/297 45/42 103/127 40/45 .33
Consanguinity
Related 455 (89.1%) 62 (71.3%) 181 (78.7%) 63 (74.2%) .001
Unrelated 56 (10.9%) 25 (28.7%) 49 (21.3%) 22 (25.8%)
Recipient age (y)
< 20 157 (30.7%) 5 (5.7%) 47 (20.5%) 5 (5.9%) .001
20-35 270 (52.9%) 35 (40.3%) 122 (53%) 34 (40%)
35-50 72 (14.1%) 37 (42.5%) 55 (23.9%) 41 (48.3%)
> 50 12 (2.3%) 10 (11.5%) 6 (2.6%) 5 (5.9%)
Donor age (y)
< 30 148 (29%) 40 (46%) 82 (35.7%) 36 (42.4%) .01
30-40 178 (34.8%) 29 (33.4%) 70 (30.4%) 25 (29.4%)
40-50 118 (23.1%) 15 (17.2%) 44 (19.1%) 15 (17.6%)
> 50 67 (13.1%) 3 (3.4%) 34 (14.8%) 9 (10.6%)
Recipient body mass index (kg/m²)
≤ 25 281 (55%) 17 (19%) 113 (49%) 21 (25%) .04
25-30 153 (30%) 45 (52%) 87 (38%) 41 (48%)
> 30 77 (15%) 25 (29%) 30 (13%) 22 (27%)
Number of blood transfusions
0 463 (90.6%) 75 (86.2%) 166 (72.1%) 60 (70.6%) .001
1-2 28 (5.5%) 10 (11.5%) 27 (11.8%) 14 (16.5%)
> 2 20 (3.9%) 2 (2.3%) 37 (16.1%) 11 (12.9%)
Blood group
Same 408 (79.8%) 68 (78.2%) 181 (78.7%) 68 (80%) .97
Different compatible 103 (20.2%) 19 (21.8%) 49 (21.3%) 17 (20%)
Pretransplant dialysis
Preemptive 67 (13.1%) 17 (19.5%) 4 (1.7%) 2 (2.4%) .001
Yes 444 (86.9%) 70 (80.5%) 226 (98.3%) 83 (97.6%)
Pretransplant medical disorders
Schistosomiasis
No 235 (46.1%) 34 (39.1%) 88 (38.3%) 26 (30.6%) .02
Yes 276 (53.9%) 53 (60.9%) 142 (61.7%) 59 (69.4%)
Original kidney disease
Chronic glomerulonephritis 52 (10.2%) 7 (8%) 25 (10.9%) 9 (10.6%) .44
Chronic pyelonephritis 44 (8.6%) 10 (11.5%) 26 (11.3%) 11 (12.9%)
Nephrosclerosis 6 (1.2%) 2 (2.3%) 1 (0.4%) 2 (2.4%)
Obstructive uropathy 33 (6.5%) 2 (2.3%) 14 (6.1%) 5 (5.9%)
Amyloidosis 10 (2%) 0 (0%) 1 (0.4%) 0 (0%)
Congenital polycystic kidneys 19 (3.7%) 6 (6.9%) 8 (3.5%) 3 (3.5%)
Hypoplasia 3 (0.6%) 2 (2.3%) 1 (0.4%) 0 (0%)
Others 153 (29.9%) 34 (39.1%) 75 (32.7%) 26 (30.6%)
Unknown 191 (37.3%) 24 (27.6%) 79 (34.3%) 29 (34.1%)
Abbreviations: DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as mean ± SD or number (%).
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34 29
35-50 years had the highest percentage of NODAT
development. Consanguinity had statistical signifi-
cance with higher percentage of unrelated donors in
both diabetic groups (P< .001). There was no
significance regarding the sex of both recipient and
donor (Table 1). Body mass index (BMI) showed a
statistical significance (P= .04); BMI < 30 kg/m²
was associated with higher incidence of NODAT
(Table 1). There was a statistical significance
regarding history of pretransplant dialysis, and HCV
antibody-positive groups had the highest percentage.
The number of blood transfusion units had a
statistical significance (P< .001) (Table 1).
#;.=;*7<95*7=6.-2,*5-2<8;-.;<*7-266>785802,
.?*5>*=287
There was a statistical significance between the 4
groups in pretransplant schistosomiasis and hyper-
tension, with the highest percentage in the HCV
antibody-positive groups (schistosomiasis, P< .001;
hypertension, P= .02) but no significance regarding
original kidney disease (P= .444) (Table 1). Therewas
a higher percentage of HLA class I (2 match; P< .001)
and HLA class II (DR, 1 match, P = .04) in the 4 groups
with high statistical signifi-cance. The HLA had not
been done with some transplant recipients who
received their transplanted kidney from a parent or
after being sure that DR matching was at least 50%,
but there was no significance regarding blood group
compatibility (P= .97) (Table 2).
-3>?*7==1.;*9B*7-266>78<>99;.<<287
A highly statistical significance was observed
between the 4 groups regarding presence and type
of adjuvant therapy (P< .001), and basiliximab
induction had the highest percentage (Table 3). There
was a statistical significance in the total dose of
steroids in the first 3 months between the different
&*+5. Immunologic Evaluation*
Human Leukocyte Antigen Group 1 Group 2 Group 3 Group 4
P
≤
(HLA) Class No: DM DM No: DM DM
HCV-Negative HCV-Negative HCV-Positive HCV-Positive
(n = 511) (n = 87) (n = 230) (n = 85)
HHLA class I (no. of matches)
0 match 20 (4%) 9 (10.1%) 12 (5.5%) 5 (6%) .001
1 match 52 (9.3%) 17 (19.6%) 37 (15.9%) 21 (25%)
2 match 226 (45.6%) 34 (39.2) 117 (50.1%) 39 (45.3%)
3 match 56 (10.2%) 7 (8.1%) 21 (9.6%) 11 (13.1%)
4 match 49 (9.9%) 12 (14%) 13 (5.9%) 6 (7.1%)
Inapplicable 108 (21%) 8 (9%) 30 (13%) 3 (3.5%)
HHLA class II (DR) (no. of matches)
1 match 415 (81%) 65 (73.6%) 196 (84.8%) 71 (82.5%) .04
2 match 96 (19%) 22 (26.4%) 34 (15.2%) 14 (17.5%)
Abbreviations: DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as number (%).
&*+5. Adjuvant Therapy*
Adjuvant Therapy Group 1 Group 2 Group 3 Group 4
P
≤
No: DM DM No: DM DM
HCV-Negative HCV-Negative HCV-Positive HCV-Positive
(n = 511) (n = 87) (n = 230) (n = 85)
Adjuvant therapy
No 45 (8.8%) 9 (10.3%) 25 (10.9%) 7 (8.2%) .001
Yes 466 (91.2%) 78 (89.7%) 205 (89.1%) 78 (91.8%)
Type of adjuvant therapy
Antithymocyte globulin
No 486 (95.1%) 80 (92%) 204 (88.7%) 68 (80%) .001
Yes 25 (4.9%) 7 (8%) 26 (11.3%) 17 (20%)
Basiliximab
No 110 (21.5%) 25 (28.7%) 70 (30.4%) 29 (34.1%)
Yes 401 (78.5%) 62 (71.3%) 160 (69.6%) 56 (65.9%)
Daclizumab
No 508 (99.4%) 86 (98.9%) 217 (94.3%) 82 (96.5%) .001
Yes 3 (0.6%) 1 (1.1%) 13 (5.7%) 3 (3.5%)
Alemtuzumab
No 474 (92.8%) 79 (90.8%) 224 (97.4%) 83 (97.6%) .01
Yes 37 (7.2%) 8 (9.2%) 6 (2.6%) 2 (2.4%)
Abbreviations: DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as number (%).
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34 Exp Clin Transplant
30
groups (P= .04) (Table 4). Regarding steroid and
sirolimus therapy between the 4 groups, high statis-
tically significant differences were observed (P < .001),
with lower significance regarding mycophenolate
mofetil (P= .04) and no significance regarding
azathioprine, cyclosporine, or tacrolimus (Table 5).
#8<==;*7<95*7= 52?.; <=*=>< 0;*/= />7,=287 *7-
<>;?2?*5
The posttransplant liver status judged by alanine
aminotransferase level showed no statistically
significance (P= .08) (Table 6). Mean serum creatinine
and creatinine clearance at last follow-up was highly
significant between the 4 groups (P≤ .001). A statistical
significance was observed regarding the condition at
last follow-up (P< .001), and living with a
functioning graft had the highest percentage in the 4
conditions (P< .001) (Table 7).
All factors that had a significant value in the
univariate analysis between the 4 groups were
studied with multivariate analysis, and only
Dose of Steroids Group 1 Group 2 Group 3 Group 4
P
≤
No: DM DM No: DM DM
HCV-Negative HCV-Negative HCV-Positive HCV-Positive
(n = 511) (n = 87) (n = 230) (n = 85)
Steroid
No 155 (30.3%) 17 (19.5%) 42 (18.3%) 7 (8.2%) .001
Yes 356 (69.7%) 70 (80.5%) 188 (81.7%) 78 (91.8%)
Tacrolimus
No 237 (46.4%) 36 (41.4%) 113 (49.1%) 36 (42.4%) .54
Yes 274 (53.6%) 51 (58.6%) 117 (50.9%) 49 (57.6%)
Cyclosporine
No 284 (55.6%) 54 (62.1%) 123 (53.5%) 51 (60%) .46
Yes 227 (44.4%) 33 (37.9%) 107 (46.5%) 34 (40%)
Mycophenolate mofetil
No 234 (45.8%) 42 (48.3%) 83 (36.1%) 42 (49.4%) .04
Yes 277 (54.2%) 45 (51.7%) 147 (63.9%) 43 (50.6%)
Azathioprine
No 354 (69.3%) 63 (72.4%) 174 (75.7%) 62 (72.9%) .34
Yes 157 (30.7%) 24 (27.6%) 56 (24.3%) 23 (27.1%)
Sirolimus
No 466 (91.2%) 67 (77%) 189 (82.2%) 56 (65.9%) .001
Yes 45 (8.8%) 20 (23%) 41 (17.8%) 29 (34.1%)
Abbreviations: DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as number (%).
&*+5. Maintenance Primary Immunosuppression Protocol*
20>;. Development of Diabetes Mellitus in Hepatitis C-Positive and
Negative Patients
20>;.Graft Survival
&*+5. Total Dose of Steroids in the First 3 Months*
Dose of Steroids Group 1 Group 2 Group 3 Group 4 P≤
No: DM DM No: DM DM
HCV- HCV- HCV- HCV-
Negative Negative Positive Positive
(n = 511) (n = 87) (n = 230) (n = 85)
Total dose of steroids 3.5 ± 1.8 3.4 ± 1.3 3.3 ± 1.6 3.9 ± 2.1 .04
in 3 mo (g)
Total dose of steroid
< 5 g 428 (83.8%) 79 (90.8%) 206 (89.5%) 66 (77.6%) .02
5-10 g 82 (16%) 8 (9.2%) 22 (9.6%) 19 (22.4%)
> 10 g 1 (0.2%) 0 (0%) 2 (0.9) 0 (0%)
Abbreviations: DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as mean ± SD or number (%).
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34 31
recipient age, total dose of steroid in the first 3
months posttransplant, time to diuresis, sirolimus
for primary immunosuppression, and adjuvant
therapy were significant on multivariate analysis
(Table 8).
The percentage of development of NODAT was
greater in the HCV-positive group (27%) than HCV-
negative group (14.5%) with high significance
(P< .001) (Figure 1). The 4 groups had statistically
significant differences in graft survival (P= .012)
(Figure 2).
Discussion
The NODAT also is known as posttransplant DM,
transplant-associated hyperglycemia, or new-onset DM,
and is a common metabolic complication post-
transplant. The incidence ranges from 2% to 53%,
reflecting wide variations in the definition of
the disorder, population, and immunosuppressive
regimen.6
In our study, frequency of development of DM
was greater in the HCV-positive (27%) than HCV-
&*+5. Posttransplant Liver Status Determined by Alanine Aminotransferase Level*
Posttransplant Liver Status Group 1 Group 2 Group 3 Group 4
P
≤
No: DM DM No: DM DM
HCV-Negative HCV-Negative HCV-Positive HCV-Positive
(n = 511) (n = 87) (n = 230) (n = 85)
Persistently normal ALT 444 (87%) 74 (85%) 170 (74%) 60 (71%) .08
Transient ALT elevation 21 (4%) 3 (3%) 7 (3%) 2 (1.5%)
Persistently high ALT 46 (9%) 10 (12%) 53 (23%) 23 (26.5%)
Abbreviations: ALT, alanine aminotransferase; DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as mean ± SD or number (%).
&*+5. Posttransplant Liver Status Determined by Alanine Aminotransferase Level*
Posttransplant Liver Status Group 1 Group 2 Group 3 Group 4
P
≤
No: DM DM No: DM DM
HCV-Negative HCV-Negative HCV-Positive HCV-Positive
(n = 511) (n = 87) (n = 230) (n = 85)
Serum creatinine at last 1.95 ± 2.36 1.81 ± 1.99 2.51 ± 2.50 2.82 ± 2.82 .001
follow-up (mg/dL)
Creatinine clearance at last 76.01 ± 31.03 67.77 ± 24.74 63.32 ± 31.64 60.93 ± 32.24 .001
follow-up (mL/min)
Condition of last follow-up
Living with functioning graft 456 (89.3%) 81 (93.1%) 171 (76.9%) 62 (73.4%) .001
Living on dialysis 43 (8.3%) 5 (5.7%) 45 (19.8%) 17 (20.5%)
Died with functioning graft 7 (1.4%) 0 (0%) 6 (2.9%) 4 (4.9%)
Died with failed graft 5 (1%) 1 (1.1%) 1 (0.4%) 1 (1.2%)
Abbreviations: DM, diabetes mellitus; HCV, hepatitis C virus
*Data reported as mean ± SD or number (%).
&*+5. Multivariate Analysis
Parameter Regression Estimate (B) Standard Error Relative Risk (95% P ≤
Confidence Interval)
Exp (B) (lower, upper)
Recipient age by group (y)
20 ------ ------ 1
20-35 1.221 0.375 3.392 .001
35-50 2.345 0.382 10.434 .001
> 50 2.897 0.528 18.119 .001
Total dose of steroid (g)
5 ------ ------ 1
5-10 0.682 0.294 1.978 .02
> 10 -19.779 2.202 0.000 .99
Time of diuresis
Immediate ------ ------ 1
Delayed 0.874 0.387 2.398 .02
Sirolimus-based primary
immunosuppression protocol -0.721 0.233 0.486 .002
Adjuvant therapy
No ------ ------ 1
Yes 1.992 0.855 1.14 .99
negative group (14.5%) (P< .001). This finding was
similar to results reported by other investigators.7-9 In
1 study, HCV-positive recipients had a significantly
lower insulin sensitivity (3.0 ± 2.1min−1.μU.mL−1.104)
than HCV-negative recipients (4.9 ± 3.0 min−1.
μU.mL−1.104; P= .02), but insulin secretion and
hepatic insulin uptake were not significantly
different.10 It is possible that HCV could induce
glucose intolerance indirectly by causing cirrhosis or
advanced fibrosis by several mechanisms, including
decreased glucose uptake as a result of splanchnic
shunting and increased gluconeogenesis.10 This is a
logical conclusion, given the observation that other
forms of liver disease associated with cirrhosis lead to
DM.11 In some surveys, NODAT was more frequent
in anti-HCV-positive than negative recipients, but no
statistical relation between HCV and posttransplant
DM was obtained.12,13 This could be related to the
type of immunosuppressive therapy and other
factors, such as the limited number of anti-HCV-
positive renal transplant recipients, low occurrence
of NODAT, short posttransplant follow-up, and
successful antiviral therapy before renal trans-
plant.14,15 Therefore, monitoring and prevention of
diabetes, coupled with treatment of HCV-infected
patients with combination antiviral therapy, should
be essential targets after transplant.16
In this study, we found a relation between
NODAT and total dose of steroids. We reported that
HCV-positive patients who developed NODAT
received a total dose of 3.9 ± 2.1 g in the 3 months
posttransplant and patients who did not develop
NODAT received 3.3 ± 1.6 g (P= .04; Table 4), and
this confirmed by multivariate analysis (Table 8). Our
results agree with previously reported results.17,18
The cause of corticosteroid-related NODAT was
assumed to be the stimulation of gluconeogenesis
and impairment of glucose uptake by muscles and
adipose tissues, which would lead to insulin
resistance. During the cyclosporine era, the incidence
of NODAT decreased to 3% to 20%.19 Our study was
in disagreement with several studies that did not find
any effect of cumulative corticosteroid doses on the
appearance of NODAT, and that reported that the
only risk factor retained for persistent impaired
fasting glucose or DM beyond the first year was a
higher number of trough levels of tacrolimus > 15
ng/mL during the first month after transplant.20-23
These studies did not exclude positive family history
of diabetes as a risk factor and used deceased donors.
The observed significant association between
HCV infection and NODAT has been linked to the
use of calcineurin inhibitors, and several investigators
suggested an association between HCV and
tacrolimus-induced DM after renal transplant.10,24,25
Although these studies provided strong evidence of
an association between tacrolimus-induced NODAT
and HCV, they did not give any evidence for the
possible underlying mechanism. This relation was not
noted in our study and some older reports.13,26
This may be explained by the small number of
patients on tacrolimus without steroids and the short
posttransplant duration of recipients on steroid-free
immunosuppression because we used a different
immunosuppressive protocol.
Our multivariate analysis confirmed the signifi-
cant role of sirolimus in the association between HCV
and NODAT. Conversion to sirolimus from tacrolimus
or cyclosporine has been associated with a significant
worsening, rather than improvement, in insulin
resistance.27 Sirolimus appears to be diabetogenic.28
This study is in agreement with a prospective study
on 26 kidney transplant recipients who were
converted from cyclosporine to sirolimus and 15
recipients who were treated with tacrolimus plus
sirolimus and discontinued tacrolimus; the switch to
sirolimus was associated with 30% increased incidence
of impaired glucose tolerance and the development of
4 cases of NODAT as a result of a defect in the
compensatory cell response and a decrease in insulin
sensitivity.29 In contrast, lower rates of NODAT have
been documented in efficacy studies of combination
therapy with alternative medications such as
mycophenolate mofetil and sirolimus.30-31 These
findings could be explained by the relatively larger
doses of corticosteroids, high levels of calcineurin
inhibitors in the early posttransplant period, different
races, and different lifestyles of the studied patients.
In our study, we detected an important effect of
adjuvant therapy on the rate of development of
NODAT, especially when basiliximab was used as an
induction agent (P< .001). These results are in
accordance with a previous report in renal transplant
patients who received basiliximab plus prednisone,
cyclosporine, and mycophenolate; NODAT, glucose
intolerance, and impaired fasting glucose were
observed at rates significantly higher than observed
in patients receiving prednisone, cyclosporine, and
mycophenolate without basiliximab.32 This could be
explained because basiliximab is an antibody
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34 Exp Clin Transplant
32
Mohamed H. Abbas et al/Experimental and Clinical Transplantation (2015) 1: 26-34
directed against the interleukin 2 (IL-2) receptor
(CD25) and suppresses CD25+CD4+ T lymphocytes.
T lymphocytes are thought to be involved in the
complex immunology causing type 2 DM.33,34
Additionally, administration of IL-2 agonists has
prevented DM in experimental studies.35
Several risk factors for NODAT were described,
and age was the most important factor. A 2-fold
increased risk in patients older than 45 years and
3-fold risk in patients older than 63 years at
transplant were reported.36 We found a statistical
significance between the 4 groups regarding recipient
age (P< .001) and donor age (P= .0029), and
multivariate analyses confirmed the role of age in
occurrence of DM after renal transplant, in
agreement with previous reports.25,26 This result is in
agreement with a previous study of 2078 nondiabetic
renal transplant recipients treated with cyclosporine
and prednisone, in a single center in the United
States, that showed that recipient age > 45 years was
associated with a 2-fold increased risk of developing
NODAT (P< .0001).37 Data from the United States
Renal Data System showed that first kidney transplant
recipients aged between 45 and 59 years had a 1.9
relative risk for NODAT (P< .0001), whereas patients
who were aged ≥ 60 years had a 2.6 relative risk
(P< .0001).38 However, in our study, the mean age for
HCV-positive recipients with NODAT was 35 to 50
years (P< .001), and this difference can be attributed
to our selection of younger patients who are expected
to resume professional activities after transplant.
In this work, we observed that the increased HLA
mismatches and DR mismatches were associated with
an increased risk of NODAT. There was a higher
percentage of HLA (2 match) (P< .001) and DR
(1 match) (P= .04) in the 4 groups with high statistical
significance, similar to results reported by other
investigators.16,19,38 A few studies have not found a
correlation between the degree of HLA mismatch and
risk of NODAT.39 These findings could be explained
by different races and use of deceased donors.
In our study, there was a statistical significance
regarding serum creatinine and creatinine clearance
at last follow-up (P< .001). The 10-year graft survival
was higher in patients who were HCV-negative
with NODAT (group 2) (Figure 2), with statistical
significance between the 4 groups (P= .012), and this
was similar to a previous study that found no
difference regarding graft survival6but unlike several
studies that reported that NODAT had been
associated with worse graft outcomes.40,41 This
difference can be attributed to the fact that graft
function was measured only by serum creatinine level.
Some of the limitations of this study were that the
HCV diagnosis was based on the serum HCV
antibody, and not serum HCV RNA polymerase
chain reaction, and only 13 patients had successful
pretransplant antiviral therapy. We feel that this
reflects typical clinical practice.
In summary, NODAT is a common complication
in renal allograft recipients. In our study there was a
positive correlation between the development of
NODAT and pretransplant HCV-positive status
because the percentage of NODAT development was
significantly greater in the HCV-positive group (27%)
than HCV-negative group (14.5%).
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