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Keywords:

  • body mass index;
  • case-control;
  • immunosuppression;
  • post-transplant diabetes mellitus;
  • renal transplant;
  • risk factors

Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

Aim of the present study was to assess, in a pair-matched analysis design, risk factors for post-transplant diabetes mellitus (PTDM) in renal transplant recipients (KTx). The incidence of PTDM was evaluated in 538 consecutive KTx in relation to their baseline immunosuppression. PTDM was defined according to the 2003 American Diabetes Association and World Health Organization experts committee definition. As risk factors for PTDM development were considered: age, family history of diabetes, body mass index (BMI), baseline immunosuppression, doses and blood levels of the immunosuppressive agents used. Baseline immunosuppression consisted of CSA, TAC and SRL + CNI. Thirty-two pair-matched controls were identified among the 538 KTx and included in the risk analysis. Significant risk factors for the development of PTDM were identified in the family history of diabetes (P < 0.02) and BMI (P < 0.05). Higher BMI and positive family history for diabetes mellitus were significant risk factors for the development of PTDM, regardless of the immunosuppressive agent used.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

Post-transplant diabetes mellitus (PTDM) is a major adverse effect of current immunosuppression after kidney transplantation. The incidence of PTDM reported in the literature is wide, between 2% and 53% [1–4] and varies according to the definition of diabetes mellitus adopted, the type of immunosuppressive medications used and other factors. Although there are currently no clearly established risk factors for PTDM, a number of characteristics have been identified that appear to predispose patients to the development of this condition [5] such as age, ethnicity, obesity, glucose intolerance, family history of diabetes and hepatitis C virus pretransplant infection.

Aim of the present study was to assess potential risk factors for PTDM in a pair-matched cohort of renal transplant recipients (KTx) treated with different immunosuppressive regimens.

Materials and methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

The incidence of PTDM was retrospectively evaluated in 538 consecutive KTx performed at the Catholic University of Rome, Italy from January 1981 to December 2002. Baseline immunosuppression was azathioprine (AZA) in 62 patients (11.5%), cyclosporine (CsA) in 328 patients (60.9%), tacrolimus (TAC) in 92 patients (17.1%) and sirolimus + calcineurine inhibitors (SRL + CIN) in 48 patients (8.9%). All patients received steroids for induction and prednisone dosage was tapered in order to reach a standard maintenance dose of 5 mg/day by the end of the third postoperative month. Over 90% of patients were on continuous steroid maintenance therapy, <10% of patients were included in steroid-free experimental protocols, PTDM was defined according to the American Diabetes Association (ADA) and World Health Organization (WHO) experts committee definition [6] as fasting blood glucose levels of 126 mg/dl or greater was confirmed by repeated testing on a different day.

Thirty-six KTx developing PTDM were identified within the entire cohort and four of these were considered noneligible for the present analysis, because of incomplete data or lack of appropriate matched controls. The remaining 32 were included in the study along with 32 pair-matched controls. Pair-matched controls were selected by age at transplant (±2 years) and date of transplantation (±6 months). Patients’ characteristics within the two groups are presented in Table 1. There were no discordant pairs. Patients with diabetic pretransplant were excluded from the present analysis. As risk factors for PTDM development were considered: recipient age at the time of transplantation, family history of diabetes, body mass index (BMI), baseline immunosuppressive agents, their doses and blood levels at predefined time points (6 months, 1, 3, 5 years post-transplant). Data were entered into an Excel (Microsoft) database and queried as appropriate for median or mean ± SD. Paired Student's t-test and chi-square test were used to compare the differences between the measurements, multiple regression analysis was also performed using Smith's Statistical Package (version 2.5 by Gary Smith, Pomona College, Claremont, CA, USA) to assess the independent contribution of the risk factors.

Table 1.  Patient demographics and immunosuppressive agents used.
ParametersPTDMControlsP
  1. *Statistically significant.

  2. PTDM, post-transplant diabetes mellitus; BMI, body mass index; TAC, tacrolimus; CsA, cyclosporine; SRL, sirolimus; CIN, calcineurine inhibitors; AZA, azathioprine; NS, not significant; MMF, mycophenolate mofetil.

No. of patients3232 
Age46 ± 1246 ± 10NS
Sex20M/12F19M/13FNS
Family history 8 20.03
BMI25 ± 3.922.2 ± 6.10.05*
Time post-Tx49.7 ± 16.550.3 ± 14.7NS
TAC1111NS
CsA2121NS
SRL + CIN 8 7NS
Steroids3129NS
MMF 4 7NS
AZA 2 2NS

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

There were no differences between the two groups in terms of age, sex, baseline immunosuppressive agents, their doses and blood levels at 6 months, 1, 3 and 5 years post-transplantation (Tables 1 and 2). Mean follow-up of KTx in the study group was 50.1 ± 6.5 months (range 17–60).

Table 2.  Blood levels of immunosuppressive agents.
 Patients (n)PTDMPatients (n)ControlsP
  1. PTDM, post-transplant diabetes mellitus; CsA, cyclosporine; TAC, tacrolimus; NA, not available.

CsA C0 blood levels
Discharge21373 ± 24221461 ± 3310.40
3 m21222 ± 14821252 ± 1160.39
6 m21253 ± 16220254 ± 1340.96
1 year21276 ± 16220202 ± 1670.10
3 year19234 ± 16819193 ± 890.13
5 year17139 ± 8117151 ± 710.26
TAC C0 blood levels
Discharge1113.7 ± 7.31111.3 ± 80.49
3 m1111.6 ± 4.91010.8 ± 4.60.86
6 m109.3 ± 5.1109.3 ± 6.10.62
1 year97.8 ± 4.697.1 ± 4.80.90
3 year79.7 ± 3.197.2 ± 4.90.17
5 year NA NA 

PTDM

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

Thirty-one patients required insulin treatment (three in AZA, 16 in CsA, six in TAC and six in SRL + CIN) and five patients required oral antidiabetic medications (zero patients in AZA, three in CsA, one in TAC, one in SRL + CIN) to normalize their blood glucose. The incidence of family history of diabetes was higher in the PTDM group compared to controls: eight (25%) vs. two (6.2%) patients, (P < 0.03); mean BMI was also higher in this group (25 ± 3.9 vs. 22.9 ± 6.1, P = 0.05). PTDM occurred 25.3 ± 38 months after transplantation, the time of onset was significantly shorter (P = 0.003) in the TAC group (2.1 ± 1.7 months post-Tx, range 0–4.3 months) compared with CsA (27.8 ± 24 months post-Tx, range 0–52.9 months). In six of 32 patients (18.7%) Table 3 PTDM disappeared 11 ± 21 months after onset (range 8.1–32.4 months), spontaneously in four patients and after steroid withdrawal in two patients. Disappearance of PTDM occurred at an earlier time in 1 patient on TAC (8.1 months) versus five patients on CsA (22.4 ± 8.5 months). Multivariate analysis of the potential risk factors for the development of PTDM was conducted by matching the dependent variable PTDM with a series of recipient demographic and immunosuppressive factors: age, BMI, family history of diabetes, serum creatinine, type of immunosuppressant (TAC, CsA or SRL), immunosuppressive drug doses and blood levels. Again two significant risk factors for the development of PTDM were identified: family history of diabetes and BMI (P < 0.02 and P < 0.05, respectively) (Table 4).

Table 3.  Characteristics of patients with PTDM disappearance.
 PTDM disappearedPTDM nondisappearedNo PTDM matched controls
  1. PTDM, post-transplant diabetes mellitus; BMI, body mass index; TAC, tacrolimus; CsA, cyclosporine; SRL, sirolimus; CIN, calcineurine inhibitors; NA, not available.

No. of patients 62632
Time since Tx (months)51.3 ± 14.749.6 ± 16.450.3 ± 14.7
Time of PTDM onset11 ± 2110 ± 15.1NA
Time of PTDM disappearance (months)18.2 ± 12.2NANA
On maintenance steroid therapy 4/6 (66%)26/26 (100%)30/32 (94%)
Immunosuppression
CsA 41417
TAC 1 5 8
SRL + CIN 1 7 7
Family history of diabetes40%33% 6%
BMI25.8 ± 1.925 ± 422.2 ± 6.1
Table 4.  Multiple regression analysis of PTDM risk factors.
ParametersCoefficientStandard errort-ValueP
  1. *Statistically significant.

  2. PTDM, post-transplant diabetes mellitus; BMI, body mass index; TAC, tacrolimus; CsA, cyclosporine; SRL, sirolimus; CIN, calcineurine inhibitors.

Age0.00600.00690.86500.1958
Sex−0.05070.13810.36680.3577
Family history0.039670.20221.96210.0279*
BMI0.03960.84341.94340.0104*
Creatinine−0.12960.08681.49230.0712
TAC0.01010.14460.06950.4724
CsA−1.14240.81821.39630.0844
SRL + CIN−0.00540.15130.03570.4859
Steroids0.21280.30110.70660.2417

Renal function, graft and patient survival

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

Renal function, graft and patient survival at 6 months, 1, 3, 5 years from transplantation were not different in the two groups (Figs 1 and 2). Mean serum creatinine levels decreased from 1.9 ± 0.6 mg/dl at discharge to 1.5 ± 0.4 mg/dl at the latest follow-up in the PTDM group and from 1.7 ± 0.9 to 1.5 ± 0.5 at the latest follow-up in controls. Five years of patient survival was slightly lower in PTDM that in controls (90% vs. 94.8%P = 0.58), but not statistically different. Five years graft survival in PTDM and in controls was 85% and 84.3% (P = 0.94) respectively (Fig. 2).

image

Figure 1. Graft function.

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Figure 2. Patient and graft survival.

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Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References

This study evaluated risk factors for the development of PTDM after renal transplantation. The incidence of PTDM reported in the literature ranges between 2% and 53% [10] depending on the definition of diabetes adopted. We adopted the American Diabetes Association (ADA) and World Health Organization (WHO) experts committee definition of diabetes [6], to decide on PTDM. The present analysis revealed that higher BMI and positive family history for diabetes mellitus are the significant risk factors for the development of PTDM, regardless of the immunosuppressive agent used. It has been previously demonstrated that the type of immunosuppression can explain up to 74% of the variability in diabetes incidence [7], but in our study the immunosuppressive agent did not emerge as a significant risk factor for PTDM development. A possible explanation for this finding is the low doses of steroid administered in our protocols and the use of meticulous therapeutic blood level monitoring of the immunosuppressive agents, avoiding prolonged high CNI exposure, a well-known hazard. In particular, levels of immunosuppression were not significantly different between patients with or without PTDM. However, a difference became clear between CsA and TAC on the timing of PTDM onset: in TAC patients PTDM occurred soon after Tx, while in CsA patients PTDM appeared to be a late complication. BMI is a well-recognized risk factor for wound and cardiovascular complications after renal transplantation, our data indicate that BMI is also a potent risk factor for PTDM development. Therefore, patients with higher BMI should be convinced to reduce their weight before transplantation. PTDM has been associated with reduced graft function, reduced patient survival and increased graft loss [8,9]. Previous study has also indicated that the consequences of post-transplant diabetes mellitus are similar to those of pretransplant diabetes mellitus [10]. We were not able to show a significant detrimental effect of PTDM on graft and patient survival. A possible explanation could be the early diagnosis and the prompt treatment of PTDM adopted, which may have avoided severe damages induced by prolonged unrecognized hyperglycaemia. Therefore, early detection, prevention and treatment of diabetes mellitus are essential to reduce the frequency of severe complications in renal transplant recipients.

In conclusion, we suggest that high BMI and family history of diabetes are the most important factors in the development of PTDM, regardless of the baseline immunosuppressive agents. In these high risk patients the immunosuppressive regimen should be carefully monitored to avoid toxic combinations, favouring the development of PTDM, and every effort should be encouraged towards an early diagnosis of PTDM.

References

  1. Top of page
  2. Summary
  3. Introduction
  4. Materials and methods
  5. Results
  6. PTDM
  7. Renal function, graft and patient survival
  8. Discussion
  9. References
  • 1
    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: 220.
  • 2
    Sumrani NB, Delaney V, Ding ZK, et al. Diabetes mellitus after renal transplantation in the cyclosporine era: an analysis of risk factors. Transplantation 1991; 51: 343.
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    Rao M, Jacob CK, Shastry JC. Post-renal transplant diabetes mellitus: a retrospective study. Nephrol Dial Transplant 1992; 7: 1039.
  • 4
    Egeland T, Fauchald P. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 1997; 64: 979.
  • 5
    Davidson J, Wilkinson A, Dantal A, et al. New-onset diabetes after transplantation: 2003 international consensus guidelines. Transplantation 2003; 75: SS3.
  • 6
    The expert committee on the diagnosis and classification of diabetes mellitus. Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 2003; 26(Suppl. 1): S5.
  • 7
    Montori VM, Velosa JA, Basu A, et al. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002; 25: 583.
  • 8
    Boudreaux JP, McHugh L, Canafax DM, et al. The impact of cyclosporine and combination immunosuppression on the incidence of posttransplant diabetes in renal allograft recipients. Transplantation 1987; 44: 376.
  • 9
    Roth D, Milgrom M, Esquenazi V, Fuller L, Burke G, Miller J. Posttransplant hyperglycemia: increased incidence in cyclosporine-treated renal allograft recipients. Transplantation 1989; 47: 278.
  • 10
    Miles AM, Sumrani N, Horowitz R, et al. Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes? Transplantation 1998; 65: 380.