Академический Документы
Профессиональный Документы
Культура Документы
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.
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.
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.
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%
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
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.
100%
No tacrolimus (n = 8874)
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
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
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
Year
published
Diabetes
definition
Years of
follow up
Boudreaux (3)
1987
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
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.
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.
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
15.
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
185