Copyright

American Journal of Transplantation 2003; 3: 178--185

Blackwell Munksgaard

Blackwell Munksgaard 2003

ISSN 1600-6135

Diabetes Mellitus after Kidney Transplantation

in the United States
Bertram L. Kasiskea,b,*, Jon J. Snydera, David
Gilbertsona and Arthur J. Matasa,c

Received 28 March 2002, revised and accepted for

publication 6 September 2002

The United States Renal Data System Coordinating Center,

Minneapolis, MN
Department of Medicine, Hennepin County Medical Center,
Minneapolis, MN
c
Department of Surgery, University of Minnesota,
Minneapolis, MN
*Corresponding author: Bertram L. Kasiske,kasis001@
umn.edu
b

New onset diabetes is a major complication after

kidney transplantation. However, the incidence, risk
factors and clinical relevance of post-transplant
diabetes mellitus (PTDM) vary among reports from
single-center observational studies and clinical trials.
Using data from the United Renal Data System we
identified 11 659 Medicare beneficiaries who received
their first kidney transplant in 19962000. The cumulative incidence of PTDM was 9.1% (95% confidence
interval = 8.69.7%), 16.0% (15.316.7%), and 24.0%
(23.124.9%) at 3, 12, and 36 months post-transplant,
respectively. Using Coxs proportional hazards
analysis, risk factors for PTDM included age, African
American race (relative risk = 1.68, range: 1.521.85,
p < 0.0001), Hispanic ethnicity (1.35, range: 1.191.54,
p < 0.0001), male donor (1.12, range: 1.031.21,
p = 0.0090), increasing HLA mismatches, hepatitis C
infection (1.33, range: 1.151.55, p < 0.0001), body
mass index 30 kg/m2 (1.73, range: 1.571.90,
p < 0.0001), and the use of tacrolimus as the initial
maintenance immunosuppressive medication (1.53,
range: 1.291.81, p < 0.0001). Factors that reduced
the risk for PTDM included the use of mycophenolate mofetil, azathioprine, younger recipient age,
glomerulonephritis as a cause of kidney failure, and
a college education. As a time-dependent covariate
in Cox analyses that also included multiple other
risk factors, PTDM was associated with increased
graft failure (1.63, 1.461.84, p < 0.0001), deathcensored graft failure (1.46, 1.251.70, p < 0.0001),
and mortality (1.87, 1.602.18, p < 0.0001). We conclude that high incidences of PTDM are associated
with the type of initial maintenance immunosuppression, race, ethnicity, obesity and hepatitis C
infection. It is a strong, independent predictor of
graft failure and mortality. Efforts should be
made to minimize the risk of this important
complication.
Key words: Diabetes mellitus, kidney transplantation,
tacrolimus, mycophenolate mofetil, azathioprine,
obesity, African American, Hispanic
178

Introduction
Although new immunosuppressive medications have
greatly improved short-term graft survival after kidney
transplantation, morbidity and mortality remain high.
Recent evidence has suggested that post-transplant diabetes mellitus (PTDM) has become increasingly common
after kidney transplantation (1), and PTDM may adversely
affect patient (24), and graft survival (5,6). A number
of risk factors for PTDM have been identified in singlecenter, retrospective, observational or case-control studies.
These include obesity (1,3,7), age (3), race (3), ethnicity (8),
family history (9,10), donor source (cadaver vs. living) (3,8),
acute rejection (1,5,814), the dose of corticosteroids
(7,10), and the type of immunosuppressive agents used
to prevent and treat rejection (1,5,810,12,13,15).
Although the best method for determining the incidence
of PTDM associated with the use of different immunosuppressive agents is from randomized controlled trials,
the results from these trials have been variable (3,1625).
In addition, the patients selected for clinical trials may not
resemble those in clinical practice. Therefore, we used
a recently validated method for identifying PTDM among
Medicare beneficiaries in the United States to examine
the incidence and clinical correlates of PTDM after kidney
transplantation (26). Results suggest that PTDM is a common, potentially preventable complication that has
adverse effects on patient and graft survival.

Methods
Patient population
We included patients in the United States Renal Data System who
received their first kidney transplant in 19962000, and had Medicare as
their primary payer. We excluded patients with other organ transplants.
Patients without Medicare as their primary payer and patients with
employer group health insurance were also excluded, because we would
be unable to identify claims that would reliably indicate the presence or
absence of diabetes. Patients were also excluded if they had diabetes at
the time of transplantation, either because diabetes was the cause of the
kidney failure or was listed as a comorbidity at the time of the kidney failure
(Center for Medicare and Medicaid Services Medical Evidence Form
number 2728) or diabetes was identified using Medicare beneficiary
claims.

Post-Transplant Diabetes Mellitus

Post-transplant diabetes mellitus

Statistical analysis

The presence of PTDM was identified using data from Medicare claims
and a previously validated method (26). This method required a minimum
of one inpatient claim, or two outpatient or part B claims within one year to
identify a patient as having diabetes. The date of onset of diabetes was
assumed to be the date of the earliest claim.

Differences between groups were tested with Students t-test or

chi-square. We examined the independent relationship between clinical
characteristics and PTDM using Coxs proportional hazards analysis. We
also examined the effect of PTDM on outcomes using Coxs proportional
hazards analysis with PTDM as a time-dependent covariate. All analyses
were carried out using the statistical software package SAS version 8.2
(SAS Institute Inc., Cary, NC). Results were considered statistically
significant for p < 0.05.

We examined a number of clinical characteristics to determine whether

they were associated with the presence or absence of PTDM. These
characteristics included patient age, race, ethnicity (Hispanic vs. nonHispanic), gender, primary cause of kidney disease (other than diabetes),
education (highest level of education achieved at the time of transplantation), employment, hepatitis C antibody status at transplantation, and obesity
(defined as body mass index
30 kg/m2). Donor characteristics included
age, race, gender and type of donor (cadaver or living). We also examined
the year of transplantation, whether or not it was performed before dialysis
(pre-emptive), the number of human leukocyte antigen mismatches,
whether or not the panel reactive antibodies were
50%, and the type
of maintenance immunosuppressive therapy that was started after
transplantation (intention-to-treat).

Maintenance immunosuppressive medications

We examined the effects on PTDM of medications that were recorded as
maintenance immunosuppression on the United Network for Organ Sharing
Kidney Transplant Recipient Registration Form (Table 1). We assumed that
the 297 (2.6%) patients who were using only methylprednisolone as maintenance immunosuppression were soon to be switched to oral prednisone.
Although it is possible that some of these patients, and some of
the remaining 278 (2.4%) who were not receiving either prednisone or
methylprednisolone, were treated with steroid-free immunosuppression,
we considered that many of these patients might have been receiving
corticosteroids despite the fact that it was not recorded. For this reason,
and because the number of these patients was very small, we did not
attempt to analyze the effect of corticosteroids on PTDM. Similarly, we did
not attempt to analyze the effects of medications used by less than 1% of
the population, e.g. SangCyA1 (Sangstat Medical Corporation, Fremont, CA),
deoxyspergualin, methotrexate and cytoxan.
Some patients received combinations of immunosuppressive medications
that more likely resulted from data entry errors than from unusual,
experimental regimens. Therefore, we excluded patients who were
reported to be receiving (1) azathioprine plus mycophenolate mofetil
(MMF), (2) cyclosporine A (CsA, Sandimmune1, Novartis Pharmaceuticals
Corporation, East Hanover, NJ) plus CsA microemulsion (Neoral1, Novartis
Pharmaceuticals Corporation, East Hanover, NJ), (3) CsA plus tacrolimus,
or (4) CsA microemulsion plus tacrolimus.

Table 1: Maintenance immunosuppressive agents

Immunosuppressive agents

Number
(total 11 659)

Percent
of total

Corticosteroids
Mycophenolate mofetil
Azathioprine
Cyclosporine microemulsion
Cyclosporine
Tacrolimus
Sirolimus
Other1

11 381
8228
1739
7269
747
2785
587
54

97.6%
70.6%
14.9%
62.4%
6.4%
23.9%
5.0%
0.5%

1
Other includes SangCyA1 (Sangstat Medical Corporation,
Fremont, CA), deoxyspergualin, cytoxan, or methotrexate.

American Journal of Transplantation 2003; 3: 178--185

Results
After excluding patients with other organ transplants, and
patients with diabetes as the primary cause of kidney failure, there were 15 787 first kidney transplants in 19962000
with Medicare as the primary payer. The 15 787 first kidney
transplants with Medicare as the primary payer, in comparison with the 21 168 patients who did not have Medicare as
their primary payer, were more likely (p < 0.0001) to be:
older (mean  SD 45  16 vs. 41  16 years); African
American (32% vs. 18%) compared with Caucasian (62% vs.
76%) or other racial groups (6% vs. 6%); Hispanic
(13% vs. 10%); a recipient of a kidney from a male donor
(56% vs. 52%); a recipient of a kidney with a greater number of HLA mismatches (3.2  1.7 vs. 2.9  1.7); hepatitis C
antibody positive (6% vs. 3%); and educated with less than
a college degree (91% vs. 82%). First kidney transplants
with Medicare as the primary payer were less likely to have
glomerulonephritis (31% vs. 34%) or polycystic kidney disease (9% vs. 14%) as the primary cause of kidney failure
(compared with other causes). Although the differences
were not great, the first kidney transplant recipients with
Medicare as the primary payer were also more likely to have
BMI
30 kg/m2 (18% vs. 17%, p 0.0185), and to receive
MMF as initial maintenance immunosuppression compared
with not receiving MMF (71% vs. 70%, p 0.0177). There
100%
95%

Survival free of diabetes

Patient and transplant characteristics

90%
85%
80%
75%
70%
65%
N = 8854

60%
0

7494
9

12

6308
15

18

5240
21

24

4258
27

30

33

36

Months post-transplant
Figure 1: Survival free of post-transplant diabetes (solid line),
with 95% confidence intervals (dashed lines). The numbers
above the X-axis indicate the total number of patients surviving
with a functioning graft free of diabetes at that time.

179

Kasiske et al.
Table 2: Independent clinical correlates of post-transplant diabetes
Characteristic
Age
017 years
1844 years
4559 years
60 years
Race
African American
Other/unknown
White
Ethnicity
Hispanic
Non-Hispanic/unknown
Donor gender
Female
Male
HLA mismatches
0
6
Obesity
Body mass index
30 kg/m2
Body mass index < 30 kg/m2
Hepatitis C
Negative/unknown
Positive
Education
College degree
No college degree/unknown
Immunosuppression
Tacrolimus
No tacrolimus
Azathioprine
No azathioprine
Mycophenolate mofetil
No mycophenolate mofetil
Cause of disease
Glomerulonephritis
Nondiabetes/unknown

Number with characteristic (%)

Relative risk for diabetes (95% CI)

p-value

(4.7%)
(46.1%)
(31.0%)
(18.1%)

0.39 (0.280.56)
1.00 reference
1.90 (1.732.09)
2.60 (2.322.92)

<0.0001

<0.0001
<0.0001

3646 (31.3%)
677 (5.8%)
7336 (62.9%)

1.68 (1.521.85)
1.51 (1.261.81)
1.00 reference

<0.0001
<0.0001

1437 (12.3%)
10 222 (87.7%)

1.35 (1.191.54)
1.00 reference

<0.0001

5199 (44.6%)
6460 (55.4%)

1.00 reference
1.12 (1.031.21)

1275 (10.9%)
816 (7.0%)

1.00 reference
1.30 (1.071.58)

2008 (17.2%)
9651 (82.8%)

1.73 (1.571.90)
1.00 reference

<0.0001

11 001 (94.4%)
658 (5.6%)

1.00 reference
1.33 (1.151.55)

<0.0001

1077 (9.2%)
10 582 (90.8%)

0.78 (0.670.90)
1.00 reference

(23.9%)
(76.1%)
(14.9%)
(85.1%)
(70.6%)
(29.4%)

1.53 (1.291.81)
1.00 reference
0.84 (0.720.97)
1.00 reference
0.78 (0.690.88)
1.00 reference

<0.0001

0.0160

<0.0001

3659 (31.4%)
10 544 (68.6%)

0.80 (0.730.88)
1.00 reference

<0.0001

551
5378
3618
2112

2785
8874
1739
9920
8228
3431

0.0090

0.0085

0.0011

Results of the Cox proportional hazards analysis, where numbers greater or less than 1.00 indicate an increased or reduced risk of
developing post-transplant diabetes, respectively. Each characteristic was adjusted for all other characteristics shown in the table,
including those with p > 0.05 (transplant year, donor age, donor source, donor race, recipient gender, cold ischemia time, panel reactive
antibody status, employability, pre-emptive transplantation, and other immunosuppressive agents; data not shown).
CI confidence interval.

were no differences (p > 0.05) between the two populations

in the use of other initial immunosuppressive agents, listed
in Table 1.
For analysis of risk factors for PTDM we excluded an
additional 3782 (24.0%) with pretransplant claims indicating
diabetes from the Medicare primary population, leaving
12 005. We also excluded 346 patients who were treated
with improbable drug combinations, leaving 11 659
patients for this analysis. The cumulative incidence of
PTDM was 9.1% (95% confidence interval 8.69.7%),
16.0% (15.316.7%), and 24.0% (23.124.9%) at 3, 12,
and 36 months post-transplant, respectively (Figure 1).
There were several clinical correlates for PTDM (Table 2).
180

However, the only potentially modifiable risk factors for

PTDM were obesity (body mass index at the time of transplantation
30 kg/m2), hepatitis C infection (as indicated
by the presence of pretransplant hepatitis C antibodies),
and the type of initial maintenance immunosuppressive
medication used.
The unadjusted cumulative incidences for PTDM at 3, 12,
and 36 months were 13.8%, 22.9%, and 35.2%, respectively, for obese patients compared with 8.2%, 14.6% and
21.8% for nonobese patients (p < 0.0001 by the log-rank
test). The effect of obesity was also significant
(p < 0.0001) after adjusting for multiple other risk factors
(Table 2). Similarly, for patients who were hepatitis C
American Journal of Transplantation 2003; 3: 178--185

Post-Transplant Diabetes Mellitus

antibody positive at transplantation, the unadjusted cumulative incidences for PTDM at 3, 12, and 36 months were
15.6%, 25.6%, and 35.4%, respectively, compared with
8.8%, 15.4% and 23.4% for patients who were hepatitis C
antibody negative at transplantation (p < 0.0001 by the
log-rank test). Hepatitis C infection was also an independent risk factor PTDM (Table 2). For patients receiving
tacrolimus the unadjusted cumulative incidences of
PTDM at 3, 12, and 36 months were 13.5%, 22.1%, and
31.8%, respectively, compared with 7.8%, 14.2%, and
21.9% for patients not receiving tacrolimus (Figure 2).
The effect of tacrolimus continued to be significant
(p < 0.0001) after adjusting for multiple risk factors
(Table 2). For patients treated initially with MMF the
unadjusted cumulative incidences of PTDM at 3, 12, and
36 months were 8.9%, 15.6%, and 23.5%, compared
with 9.7%, 17.1%, and 25.3% for patients not receiving
MMF (p 0.0236). The effect of MMF was statistically
significant (p < 0.0001) after adjusting for multiple other
risk factors (Table 2). For patients treated initially with
azathioprine the unadjusted cumulative incidences of
PTDM at 3, 12, and 36 months were 7.9%, 14.2%, and
22.2%, compared with 9.4%, 16.4%, and 24.4% for
patients not receiving azathioprine (p 0.0704). The effect
of azathioprine was statistically significant (p 0.0161)
after adjusting for multiple other risk factors (Table 2).
The unadjusted incidence of PTDM changed from 14.3%
at one year for those transplanted in 199697 to 17.3% at
one year for those transplanted in 19982000 (p 0.0029
by the log-rank test). However, the year of transplantation
was not an independent risk factor for PTDM after
adjusting for other covariates.

100%
No tacrolimus (n = 8874)

Survival free of diabetes

95%

Tacrolimus (n = 2785)

90%
p < 0.0001

85%
80%
75%
70%
65%

N = 7039
N = 1817

60%
0

6119
1375
9

5260
1049

4440
800

12 15 18 21 24 27
Months post-transplant

3681
577
30

33

36

Figure 2: Survival free of post-transplant diabetes for

patients treated without (solid black line) and with (solid
gray line) tacrolimus as initial maintenance immunosuppressive medication. The dashed lines indicate the 95%
confidence intervals. The numbers above the X-axis indicate the
total number of patients surviving with a functioning graft free of
diabetes at that time (upper row for patients treated without, and
lower row for patients treated with tacrolimus).

American Journal of Transplantation 2003; 3: 178--185

The PTDM was associated with higher rates of graft failure,

death-censored graft failure, and mortality (Table 3). These
associations were independent of the risk factors for PTDM
(Table 2), as well as multiple other risk factors for graft failure.
Interestingly, while tacrolimus was associated with a higher
rate of PTDM (Table 2), and PTDM was associated with an
increased risk for graft failure, tacrolimus was nevertheless
associated with a reduced risk for graft failure (Table 3).
Similarly, Hispanic ethnicity was associated with a higher
rate of PTDM (Table 2), but a slightly reduced risk of graft
failure.
The relative risk of PTDM (adjusted for other clinical correlates of PTDM) for the 923 deaths from any cause [1.87 (1.60
2.18), p < 0.0001], was similar to the relative risks for the 186
deaths as a result of infection [1.87 (1.312.67) p 0.0006],
the 258 deaths as a result of cardiovascular disease [1.47
(1.081.99), p 0.0140], and the 188 deaths from other
causes [1.82 (1.292.58), p 0.0007]. The relative risk of
PTDM for the 62 deaths as a result of malignancy was not
statistically significant [1.18 (0.632.20), p 0.5993], while
the relative risk for the 229 deaths of unknown causes was
2.77 (2.073.72), p < 0.0001.

Discussion
Post-transplant diabetes is a common complication of
immunosuppressive medications after kidney transplantation. Our results suggest that the incidence of PTDM
among Medicare beneficiaries is very high. However, it
is important to keep in mind that the rate of detection
of PTDM may vary depending on the methods used,
e.g. how diabetes is defined, the duration of follow
up, the types and amounts of immunosuppression
used, and the presence of pretransplant risk factors.
A recent meta-analysis of observational studies and
randomized controlled trials reported that the incidence
of PTDM (variously defined) in the first year after
transplantation varied from 2 to 50% (27). Our study
population included only Medicare beneficiaries, who had
a higher prevalence of risk factors for PTDM compared
with the non-Medicare primary population. Despite
potentially important differences between the clinical
trials and the analysis of registry data, the overall
incidence of PTDM in this study, 16.0% in one year, is in
the range (525%) reported in recent randomized
controlled trials (Table 4).
We identified several risk factors for PTDM, but only obesity,
hepatitis C infection, and the type of immunosuppressive
medications used are potentially modifiable. The risk of PTDM
was 53% greater in the patients treated with tacrolimus
compared with the patients not initially treated with
tacrolimus (Table 2). This is consistent with the findings of
randomized controlled trials, where the incidence of PTDM
has been consistently higher among patients treated with
tacrolimus compared with CsA and CsA microemulsion
181

Kasiske et al.
Table 3: Independent effects of post-transplant diabetes on graft failure
Characteristic
Post-transplant diabetes
Age
017 years
1844 years
4559 years
60 years
Race
African American
Other/unknown
White
Ethnicity
Hispanic
Non-Hispanic/unknown
Donor gender
Female
Male
HLA mismatches
0
2
3
4
5
6
Obesity
Body mass index
30 kg/m2
Body mass index < 30 kg/m2
Hepatitis C
Negative
Positive
Education
College degree
No college degree/unknown
Immunosuppression
Tacrolimus
No tacrolimus
Azathioprine
No azathioprine
Mycophenolate mofetil
No mycophenolate mofetil
Cause of disease
Glomerulonephritis
Other/unknown

Relative risk (95% Cl)

Graft failure
1

Death-censored graft failure

Death

1.63 (1.461.84)

1.46 (1.251.70)

1.87 (1.602.18)1

1.03 (0.811.32)
1.00 reference
1.02 (0.921.14)
1.48 (1.311.68)1

1.10 (0.851.44)
1.00 reference
0.75 (0.660.86)1
0.73 (0.620.88)2

0.80 (0.481.34)
1.00 reference
2.13 (1.792.54)1
4.08 (3.334.83)1

1.29 (1.161.44)1
0.78 (0.620.98)4
1.00 reference

1.67 (1.461.90)1
0.86 (0.651.15)
1.00 reference

0.86 (0.741.02)
0.63 (0.440.89)3
1.00 reference

0.77 (0.660.91)3
1.00 reference

0.92 (0.751.11)
1.00 reference

0.58 (0.440.76)1
1.00 reference

1.00 reference
0.87 (0.790.95)3

1.00 reference
0.88 (0.780.98)4

1.00 reference
0.86 (0.750.98)4

1.00 reference
1.31 (1.061.60)4
1.39 (1.151.67)2
1.65 (1.381.99)1
1.59 (1.311.93)1
1.80 (1.452.25)1

1.00 reference
1.32 (1.011.72)4
1.46 (1.151.86)3
1.73 (1.372.19)1
1.59 (1.242.04)2
1.90 (1.442.51)1

1.00 reference
1.33 (0.991.77)
1.32 (1.011.73)4
1.47 (1.131.92)3
1.60 (1.212.11)3
1.52 (1.102.12)4

1.13 (1.011.27)4
1.00 reference

1.24 (1.081.42)3
1.00 reference

1.01 (0.851.20)
1.00 reference

1.00 reference
1.24 (1.051.46)4

1.00 reference
1.15 (0.941.42)

1.00 reference
1.27 (0.991.64)

0.88 (0.751.04)
1.00 reference

0.86 (0.701.07)
1.00 reference

0.88 (0.701.11)
1.00 reference

0.70 (0.590.83)1
1.00 reference
0.90 (0.771.04)
1.00 reference
0.81 (0.710.93)3
1.00 reference

0.72 (0.580.88)3
1.00 reference
0.87 (0.721.05)
1.00 reference
0.82 (0.690.96)4
1.00 reference

0.65 (0.500.84)2
1.00 reference
0.92 (0.741.14)
1.00 reference
0.77 (0.640.93)3
1.00 reference

0.96 (0.871.06)
1.00 reference

1.00 (0.891.13)
1.00 reference

0.91 (0.781.06)
1.00 reference

Results of the Cox proportional hazards analyses, where numbers greater or less than 1.00 indicate an increased or reduced risk of graft
failure. Each characteristic was adjusted for all other characteristics, as well as transplant year, donor source (living vs. cadaver),
preemptive transplantation, gender, employability, donor age, donor race, cold ischemia time, panel reactive antibody status, employability, and other immunosuppressive agents (not shown).
1
p < 0.0001; 20.0001 p < 0.0010; 30.0010 p < 0.0100; 40.0100 p < 0.0500.

(Table 4). It is likely that some patients changed their immunosuppressive medications during the follow-up period, but in
any case the most valid analysis of the effects of immunosuppression is arguably by intention to treat. It is also possible
that the association between tacrolimus and PTDM is not
causal, and that more patients at risk for PTDM were placed
on tacrolimus. However, it seems unlikely that family history
for diabetes, or other risk factors not included in the statistical
adjustment for the risk of PTDM, would have been more
common in the patients treated with tacrolimus.
182

In contrast to the effects of tacrolimus, the use of

azathioprine and MMF were associated with 16% and
22% lower risks, respectively, for PTDM (Table 2). The
reasons for these associations are not clear, but it is
possible that the use of MMF or azathioprine allowed
clinicians to use lower doses of other immunosuppressive
medications that are more likely to cause PTDM.
One of the strongest risk factors for PTDM was
obesity (Table 2). Several retrospective, single-center,
American Journal of Transplantation 2003; 3: 178--185

Post-Transplant Diabetes Mellitus

Table 4: Incidence of post-transplant diabetes in randomized controlled trials1
First
author

Year
published

Diabetes
definition

Years of
follow up

Boudreaux (3)

1987

FBS > 140

and OGT

25

Insulin or
oral agent

1.0

Insulin or
oral agent

2.0

Scantlebury (16)
Isoniemi (17)

Ponticelli (18)
Vincenti (19)
Pirsch (20)
Mayer (21)

1991
1991

1996
1996
1997
1997

Not
Defined

10

Insulin >
1 week

1.0

Insulin >
30 days

1.0

Insulin >
30 days

1.0

Diabetes incidence (%)

n
47
58

PRED

CSA

25
25
27
21

12.0
0.02
14.3

145
303

2.1

Groth (23)

1999

Not
defined

1.0

42
41
46

AZA
AZA

13.3

4.0

106
102

AZA
AZA
AZA

12.2

151
151

1.3

3.7

5.0

Not
Defined

Other
agents
AZA
AZA

25.0

28
67

1999

SIR

6.9
7.0

Shapiro (22)

TAC

6.4

14
20

53
55

NEO

25.4

AZA
AZA

19.9

AZA
AZA

11.6

AZA
AZA

9.3
4.7

MMF

2.0
2.0
6.5

AZA
AZA
MMF

Johnson (24)

2000

Insulin >
30 days

1.0

57
42
42

14.0
6.5
19.0

AZA
MMF
AZA

Miller (25)

2000

Insulin >
30 days

1.0

41
43

12.2
4.7

MMF (1 g)
MMF (2 g)

1
The Scantlebury study did not include patients crossing over. All other studies were analyzed by intention-to-treat. Patients treated with
CSA, TAC, or SIR also received prednisone, except as noted in the Isoniemi study.
2
CsA and AZA only.
FBS fasting blood sugar, OGT oral glucose tolerance test, PRED prednisone, CSA cyclosporine, NEO CsA microemulsion,
TAC tacrolimus SIR sirolimus, AZA azathioprine, MMF mycophenolate mofetil.

observational and case-control studies have also reported

that obesity is associated with an increased risk
of PTDM (1,3,7). Lifestyle modification was recently
shown to reduce the risk of type 2 diabetes in
nontransplant patients with elevated fasting or postload
plasma glucose (28). Thus, to the extent that these
results may be applicable to kidney transplant recipients,
lifestyle modification may help to reduce the risk of
PTDM.
Diabetes has been reported to be more common in
patients with hepatitis C than in other types of liver
disease in the general population (29,30). Similarly,
hepatitis C has been associated with an increased
incidence of PTDM in liver transplant recipients (31,33),
and there is a preliminary report linking hepatitis C
and PTDM in kidney transplant recipients (34). Importantly,
successful antiviral treatment of hepatitis C in liver
transplant recipients appears to be associated with
American Journal of Transplantation 2003; 3: 178--185

improved glycemic control (35,36). This suggests that

successful pre- or post-transplant treatment of hepatitis C
could potentially reduce the incidence of PTDM after
kidney transplantation.
Age is another important risk factor for PTDM (Table 2).
Single-center, retrospective studies have consistently
found PTDM to be much more common in older compared
with younger individuals (1,3,5,810,12,13). Indeed,
PTDM was recently reported to occur in less than 3% of
children (14).
In the present study, PTDM was more common among
African Americans compared with Caucasians. This has
also been reported in single-center, retrospective studies
(1,2,8,14). Similarly, Hispanic ethnicity was associated
with a higher risk of PTDM in the current study, and this
has been reported in a single-center study (8). However,
another study reported that Hispanic children were at lower
183

Kasiske et al.
risk for PTDM compared with non-Hispanic children (14).
These inconsistencies may be because of the small
number of children with PTDM in the latter study.
Age, race and ethnicity are not modifiable risk factors, and
obesity is a risk factor that is difficult to modify. However,
the effects of risk factors are additive, and it may be
possible to reduce the overall risk of PTDM by avoiding
or reducing the doses of immunosuppressive medications
that are particularly likely to cause PTDM in patients with
these other risk factors. Of course the risk of acute
rejection must also be included in the selection of immunosuppressive medications.
It is interesting that despite the association between tacrolimus and PTDM, and the association between PTDM and
reduced graft survival, tacrolimus was nevertheless associated with improved graft survival (Table 3). Similarly, MMF
was associated with improved outcomes (Table 3). Of
course, none of these associations proves causal relationships, and to date there have been no randomized controlled trials showing that either tacrolimus or MMF
improve graft survival. In the end, only long-term follow
up of patients treated in randomized trials will allow us to
judge the relative effects of different immunosuppressive
medications on graft and patient survival.

Acknowledgements
The data reported here have been supplied by the United
States Renal Data System. The interpretation and reporting of these data are the responsibility of the authors and
in no way should be seen as an official policy or interpretation of the U.S. Government. Portions of this work were
presented at the American Society of Nephrology and
International Congress of Nephrologys joint World
Congress of Nephrology, October 16, 2001, in San
Francisco, CA.

References
1.

2.

3.

4.

Some of the associations between PTDM and graft failure

can be explained by the higher risk for death, and indeed
the relative risk associated with PTDM is higher for death
than for death-censored graft failure (Table 3). It is plausible that PTDM had a direct effect on mortality, as diabetes is associated with an increased risk for infection and
other complications that can increase mortality. Less clear
is why PTDM was associated with death-censored graft
failure. Given the relatively short period of follow up in
this study, it seems unlikely that PTDM caused deathcensored graft failure solely because of recurrence of
diabetes in the allograft. It is possible that PTDM
influenced the structure and function of the graft and
accelerated graft deterioration in ways that remain poorly
defined. However, it is even more plausible that the association between PTDM and death-censored graft survival
was the result of early acute rejection that led to both
PTDM and death-censored graft survival. Specifically, acute
rejection and/or graft dysfunction may have led to the use of
more immunosuppression that caused PTDM and (independently) a higher risk for death censored graft failure.
In summary, this study shows that there is a very high
incidence of PTDM after kidney transplantation, and that
PTDM is associated with worse outcomes. Although the
reasons for these associations may not be causal, it is
advisable to minimize the risk for PTDM after kidney
transplantation. The results of this study suggest that the
selection of immunosuppression, particularly in high-risk
patients, may be one way in which the risk of PTDM may
be reduced.
184

5.

6.

7.
8.

9.

10.

11.

12.

13.

14.

Cosio FG, Pesavento TE, Osei K, Henry ML, Ferguson RM. Posttransplant diabetes mellitus: increasing incidence in renal allograft
recipients transplanted in recent years. Kidney Int 2001; 59 (2):
732737.
Friedman EA, Shyh TP, Beyer MM, Manis T, Butt KMH. Posttransplant diabetes in kidney transplant recipients. Am J Nephrol
1985; 5: 196202.
Ascher N, Sutherland DER, Payne W et al. The impact of cyclosporine and combination immunosuppression on the incidence of
posttransplant diabetes in renal allograft recipients. Transplantation
1987; 44 (3): 376381.
Revanur VK, Jardine AG, Kingsmore DB, Jaques BC, Hamilton DH,
Jindal RM. Influence of diabetes mellitus on patient and graft
survival in recipients of kidney transplantation. Clin Transplant
2001; 15 (2): 8994.
Roth D, Milgrom M, Esquenazi V, Fuller L, Burke G, Miller J.
Posttransplant hyperglycemia. Increased incidence in cyclosporinetreated renal allograft recipients. Transplantation 1989; 47 (2):
278281.
Homel P, Maursky V, Markell MS et al. Diabetes mellitus after
renal transplantation: as deleterious as non- transplant-associated
diabetes? Transplantation 1998; 65 (3): 380384.
Jawad F, Rizvi SA. Posttransplant diabetes mellitus in live-related
renal transplantation. Transplant Proc 2000; 32 (7): 1888.
Davis R, Daskalakis P, Friedman EA et al. Posttransplant diabetes
mellitus in cyclosporine-treated renal transplant recipients.
Transplant Proc 1991; 23 (1 Part 2): 12491250.
Hathaway DK, Tolley EA, Blakely ML, Winsett RP, Gaber AO.
Development of an index to predict posttransplant diabetes
mellitus. Clin Transplant 1993; 7 (4): 330338.
Stenstrom J, Leivestad T, Egeland T et al. Glucose intolerance
after renal transplantation depends upon prednisolone dose and
recipient age. Transplantation 1997; 64 (7): 979983.
von Kiparski A, Frei D, Uhlschmid G, Largiader F, Binswanger U.
Post-transplant diabetes mellitus in renal allograft recipients:
a matched-pair control study. Nephrol Dial Transplant 1990;
5 (3): 220225.
Rao M, Jacob CK, Shastry JC. Post-renal transplant diabetes
mellitus a retrospective study. Nephrol Dial Transplant 1992;
7 (10): 10391042.
Vesco L, Busson M, Bedrossian J, Bitker MO, Hiesse C, Lang P.
Diabetes mellitus after renal transplantation: characteristics,
outcome, and risk factors. Transplantation 1996; 61 (10):
14751478.
Al-Uzri A, Stablein DM, Cohn RA. Posttransplant diabetes
mellitus in pediatric renal transplant recipients. a report of the

American Journal of Transplantation 2003; 3: 178--185

Post-Transplant Diabetes Mellitus

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.

North American Pediatric Renal Transplant Cooperative Study

(NAPRTCS). Transplantation 2001; 72 (6): 10201024.
Aikawa I, Fukuda M, Yasumura T et al. Effect of cyclosporine
on the endocrine and exocrine pancreas in kidney transplant
recipients. Am J Kidney Dis 1988; 12 (1): 1117.
Tzakis A, McCauley J, Jordan M et al. New onset of diabetes in
FK 506 vs cyclosporine-treated kidney transplant recipients.
Transplant Proc 1991; 23 (6): 31693170.
Isoniemi H. Renal allograft immunosuppression V. Glucose intolerance occurring in different immunosuppressive treatments.
Clin Transplantation 1991; 5: 268272.
Ponticelli C, Civati G, Tarantino A et al. Randomized study with
cyclosporine in kidney transplantation: 10-year follow-up. J Am
Soc Nephrol 1996; 7: 792797.
Vincenti F, Laskow DA, Neylan JF, Mendez R, Matas AJ. Oneyear follow-up of an open-label trial of FK506 for primary kidney
transplantation. A report of the U.S. Multicenter FK506 Kidney
Transplant Group. Transplantation 1996; 61 (11): 15761581.
Pirsch JD, Miller J, Deierhoi MH, Vincenti F, Filo RS. A comparison of
tacrolimus (FK506) and cyclosporine for immunosuppression after
cadaveric renal transplantation. FK506 Kidney Transplant Study
Group. Transplantation 1997; 63 (7): 977983.
Besse T, Grabensee B, Klein B et al. Multicenter randomized trial
comparing tacrolimus (FK506) and cyclosporine in the prevention of
renal allograft rejection: a report of the European Tacrolimus Multicenter Renal Study Group. Transplantation 1997; 64 (3): 436443.
Vivas C, Marsh JW, McCauley J et al. A prospective, randomized
trial of tacrolimus/prednisone versus tacrolimus/prednisone/
mycophenolate mofetil in renal transplant recipients. Transplantation 1999; 67 (3): 411415.
Calne R, Kreis H, Lang P et al. Sirolimus (rapamycin)-based therapy in
human renal transplantation: similar efficacy and different toxicity
compared with cyclosporine. Sirolimus European Renal Transplant
Study Group. Transplantation 1999; 67 (7): 10361042.
Halloran P, Stegall M, Hardy M et al. Randomized trial of tacrolimus (Prograf) in combination with azathioprine or mycophenolate
mofetil versus cyclosporine (Neoral) with mycophenolate mofetil
after cadaveric kidney transplantation. Transplantation 2000;
69 (5): 834841.
Miller J, Mendez R, Pirsch JD, Jensik SC. Safety and efficacy of
tacrolimus in combination with mycophenolate mofetil (MMF) in

American Journal of Transplantation 2003; 3: 178--185

26.

27.

28.

29.

30.

31.

32.

33.

34.

35.

36.

cadaveric renal transplant recipients. FK506/MMF Dose-Ranging

Kidney Transplant Study Group. Transplantation 2000; 69 (5):
875880.
Hebert PL, Geiss LS, Tierney EF, Engelgau MM, Yawn BP,
McBean AM. Identifying persons with diabetes using Medicare
claims data. Am J Med Qual 1999; 14 (6): 270277.
Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC.
Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002; 25 (583): 592.
Hammon RE, Lachin JM, Walker EA et al. Reduction in the
incidence of type 2 diabetes with lifestyle intervention or
metformin. Diabetes prevention program research group. New
Engl J Med 2002; 346: 393403.
Allison ME, Wreghitt T, Palmer CR, Alexander GJ. Evidence for
a link between hepatitis C virus infection and diabetes mellitus in
a cirrhotic population. J Hepatol 1994; 21 (6): 11351139.
Perret G, Richardet JP, Raffoux C et al. High prevalence of diabetes
mellitus in patients with chronic hepatitis C. A case-control study.
Gastroenterol Clin Biol 1996; 20 (67): 544548.
Knobler H, Stagnaro-Green A, Wallenstein S, Schwartz M,
Roman SH. Higher incidence of diabetes in liver transplant
recipients with hepatitis C. J Clin Gastroenterol 1998; 26 (1):
3033.
Qian K, Alexander GJ, Xu L et al. Association of diabetes mellitus
and chronic hepatitis C virus infection. Hepatology 1999; 29 (2):
328333.
Wanless IR, Hemming AW, Croxford R et al. Hepatitis C-related
cirrhosis: a predictor of diabetes after liver transplantation.
Hepatology 2000; 32 (1): 8790.
zdemir N et al. Impact of HCV
Karavelioglu D, Baysal C, O
infection on development of posttransplantation diabetes
mellitus in renal allograft recipients. Transplant Proc 2000;
32 (3): 561562.
Toffolo G, Breim D, Lormann J et al. Interferon-alpha improves
glucose tolerance in diabetic and non- diabetic patients with
HCV-induced liver disease. Exp Clin Endocrinol Diabetes 1999;
107 (6): 343349.
Baid S, Cosimi AB, Farrell ML et al. Posttransplant diabetes
mellitus in liver transplant recipients: risk factors, temporal relationship with hepatitis C virus allograft hepatitis, and impact on
mortality. Transplantation 2001; 72 (6): 10661072.

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