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Keywords:

  • Post transplant diabetes mellitus;
  • risk factors;
  • tacrolimus

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

The onset of diabetes mellitus following kidney transplantation or post-transplant diabetes mellitus (PTDM) is now recognized as being an increasingly common complication that is associated with poor graft and patient survival. The incidence and clinical correlates of PTDM in a Canadian kidney transplant population has not been examined and may vary based on differences in demographics (i.e. race). Furthermore, little information exists on the association of variables such as cmulative dose of corticosteroids and trough calcineurin inhibitor levels and PTDM. We examined all recipients of a kidney transplant in our center between 1995 and 2001 and found an overall PTDM rate of 9.8%. Five clinical factors were independently associated with PTDM: older recipient age, deceased donor, hepatitis C antibody status, rejection episode and use of tacrolimus (vs. cyclosporine). Furthermore, cmulative corticosteroid dose and calcineurin inhibitor trough level were not associated with PTDM. This study demonstrates that in a Canadian kidney transplant population that there is a significant risk of PTDM following kidney transplantation, and it is therefore advisable to minimize this risk.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Recent evidence demonstrates that post-transplant diabetes mellitus (PTDM) is an increasingly common complication of kidney transplantation (1), and is associated with poorer outcomes (2) in terms of graft (3,4) and patient survival (5–7). Furthermore, graft failure remains a significant problem, half of which is caused by patient death and the majority of these deaths are caused by cardiovascular disease (8). Diabetes amplifies the already increased risk of cardiovascular disease among kidney transplant recipients. A number of risk factors for developing PTDM have been identified in single-center, observational or case-control studies. These include age (6), race (6), ethnicity (9), family history (10,11), hepatitis C (2), obesity (1,6,12), donor source (deceased vs. living) (6,9), acute rejection (1,3,9–11,13–16), the type of immunosuppressive agents used to prevent and treat rejection (1,3,9–11,14,15,17) and the dose of corticosteroids (2,11,12,18).

Demographic characteristics of transplant recipients and healthcare delivery systems vary appreciably between Canada and the United States. In particular, differences exist in the distribution of race and/or ethnicity, homogeneous follow-up of transplant recipients in a given geographic area and a universal health care system. These differences may result in varying incidence rates and clinical correlates of PTDM and closer examination may provide an insight into how risk profiling and management of renal transplant recipients could be improved to avoid this serious complication. Also the, large registry database studies lack detailed information on variables such as hypertension, the dose and cmulative dose of corticosteroids and trough calcineurin inhibitor levels and their association with PTDM which may influence the likelihood or severity of PTDM. We now studied our center's kidney transplant population to determine the incidence and clinical correlates of PTDM following transplantation.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

Patient population

We studied all patients receiving a cadaver or living donor kidney transplant at our institution between 1 January, 1995 and 31 August, 2001. The study end date was 31 July, 2003. Patients with graft failure or death within 1 month post-transplant, multi-organ transplant recipients and patients who had a diagnosis of diabetes mellitus prior to transplant (either as native kidney disease or co-morbidity) were excluded.

Definition of post-transplant diabetes mellitus

The presence of PTDM was determined retrospectively through medical chart review and defined as two random blood sugar values ≥11.1 mmol/L and/or fasting blood sugar values ≥7.0 mmol/L, taken on separate occasions, as per published Canadian guidelines (19), which are similar to the WHO guidelines (20). We confirmed this diagnosis of diabetes by the definition of treatment with oral hypoglycemic agents or insulin continued for more than 30 days post-transplant and/or the persistence of untreated hyperglycemia for greater than 30 days. There was no difference in event rate based on the two definitions. The date of onset of diabetes was assumed to be the first date of documented abnormal blood glucose values. Blood glucose values are routinely collected at least weekly for 0–3 months, every 2–4 weeks for months 3–6 and every 3 months thereafter. Chart review of all available blood sugars were completed for purposes of diagnosing PTDM.

Clinical variables

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 and gender, year of transplant, dialysis prior to transplant, obesity (defined as a continuous variable and as body mass index (BMI) ≥30) at time of transplant and 6 months after transplant; type of donor (cadaver vs. living); delayed graft function as defined by the requirement for hemodialysis in the first week post-transplant; the number of human leukocyte antigen mismatches, induction therapy, type and dose of maintenance- immunosuppression therapy, calcineurin inhibitor trough levels, dose and cmulative dose of corticosteroid therapy, rejection episodes (defined as clinically suspected and treated and/or biopsy proven); cytomegalovirus (CMV) donor recipient mismatch status; hepatitis C antibody status at time of transplant; and presence or absence of hypertension (defined as any treatment for high blood pressure and(or a systolic value >140 or a diastolic value >90 within 2 years of transplant). We did not have information on gestational diabetes, lipid abnormalities prior to transplant or family history of diabetes.

Immunosuppression regimen

Standard immunosuppression consisted of azathioprine or mycophenolate mofetil, cyclosporine or tacrolimus and prednisone. Tacrolimus became our preferred calcineurin inhibitor choice for de novo renal transplants after 1999. During the course of the study of patients who developed PTDM, three patients were switched from cyclosporine to tacrolimus prior to developing PTDM. Once PTDM was diagnosed, two patients were switched from tacrolimus to cyclosporine but this did not result in resolution of PTDM. In the group of patients who did not develop PTDM, <15% of patients had calcineurin inhibitor switched (primarily from cyclosporine to tacrolimus for cosmetic indications such as hirsutism, gingival hypertrophy (90%) and less commonly after a rejection episode (10%)). There were no cases where calcineurin discontinuation occurred. Anti-lymphocyte globulin, OKT3 or anti-IL2 receptor antibody induction therapy was used in 27% of recipients with poor early function or at high immunologic risk due to previous grafts or anti-HLA antibodies.

Statistical analysis

SPSS 11.5 for Windows was used to perform statistical analysis. The data are expressed as mean ± S.D.. Mean values in the two groups, PTDM and no PTDM, were compared by the Student's t-test or by non-parametric tests if the data were not normally distributed. Proportions were compared by chi-square analysis. The incidence of PTDM over time post-transplant was analyzed by both univariate and multivariate Cox regression and also by Kaplan-Meier analysis after censoring patients for patient death and for graft loss. Graft survival and patient-survival analysis were also conducted by Cox regression. Patient survival was censored at the time of graft loss. The variables hypertension, steroid dose and rejection were all used as time-dependent variables in the analysis of PTDM. The variable PTDM was used as a time-dependent variable in the analysis of patient and graft survival. Results were considered statistically significant for p < 0.05.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

After excluding patients with other organ transplants (n = 2), patients with diabetes prior to transplant (n = 107) and patients who failed within the first 30 days post-transplant (n = 44) or with missing information (n = 16), there were available data on 386 adult kidney transplant recipients between 1995 and 2001 to analyze (Table 1). The majority of our patient population consists of non-black individuals (97.4%) and we had very few patients on no steroid protocols (∼3%). The median time to PTDM diagnosis was 44.2 days (ranging between 17 days and 8.7 years). We found a cmulative incidence of PTDM in our kidney transplant population of 6.7% at 6 months, 7.0% at 12 months and 8.0% at 3 years post-transplant as shown in Figure 1. Over the entire study period, the cmulative incidence rate of PTDM was 9.8% and the median time to diagnosis was 2.4 months. The average values for random blood sugar at the time of diagnosis for recipients with PTDM was 16.5 ± 9.2 mmol/L as compared to the mean blood glucose value in follow-up of 5.6 ± 1.1 mmol/L in recipients who did not develop PTDM (p < 0.001). The average value for random blood sugar at the time of transplant for recipients who subsequently developed PTDM was 6.4 ± 1.5 mmol/L, and 5.8 ± 1.6 mmol/L for individuals who did not develop PTDM (p = NS). Of the patients who developed PTDM, 63% required oral agents for treatment and 14% required insulin therapy. There was no association between the time of diagnosis and the agent used for treatment. PTDM resolved in 10.5% of the cases, as defined by discontinuation of oral agents or insulin therapy but was not related to medication changes (i.e. calcineurin inhibitor switch or prednisone withdrawal).

Table 1.  Patient and transplant characteristics
 (n = 386)%
  1. aHypertension defined as any treatment for high blood pressure and/or a systolic value >140 or a diastolic value >90 within 2 years post-transplant.

Non-black race37697.4
Age ≥ 45 years17545.5
Gender male24162.4
Transplant after 199820753.6
Number of transplant >16316.0
Pre-transplant dialysis31682.3
Hypertensiona33691.6
Hepatitis C antibody positive113.0
Polycystic kidney disease4210.9
Induction therapy10327.0
Rejection episode12131.3
Dialysis dependent 1st week post-transplant4812.5
Cytomegalovirus mismatch (D+R−)6517.0
Body mass index at transplant >304914.4
AB mismatch ≥228074.9
DR mismatch ≥128476.3
Tacrolimus (vs. CsA)10428.5
Azathioprine (vs. MMF)12432.3
Deceased donor22458.0
Disease recurrence318.1
Hematuria post-transplant11233.6
Proteinuria post-transplant8124.3
Prednisone therapy post-transplant37697.4
image

Figure 1. Cmulative incidence of de novo diabetes post-kidney transplantation.

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The overall rejection rate in our population was 30% (25% clinically suspected and treated and 75% biopsy proven). Monoclonal or polyclonal therapy for severe rejection was used in 25% of cases and the rest were treated with high dose solumedrol alone.

Clinical variables associated with PTDM

Table 2 displays the results of univariate and multivariate Cox regression analysis. In univariate analysis, the use of tacrolimus as compared to cyclosporine was associated with PTDM and the incidence of PTDM was three times higher in patients transplanted since 1998, compared with those transplanted prior to 1998, the year our program converted to preferred use of tacrolimus versus cyclosporine. Recipients who received azathioprine as compared with mycophenolate mofetil, had a lower risk of developing diabetes (HR = 0.4, p = 0.03).

Table 2.  Independent clinical correlates of post-transplant diabetes mellitus (PTDM) defined by Cox regression models
 Univariate analysis HR (95% CI)Multivariate analysis p HR (95% CI) p
  1. aHR for every 10 years of age;.bTime-dependent variable in the model; cHypertension defined as any treatment for high blood pressure and/or a systolic value >140 or a diastolic value >90 within 2 years post-transplant.

Agea1.5.(1.2–1.8)0.0021.5 (1.1–1.9)0.006
Deceased (vs. living) donor3.3 (1.46–7.52)0.0043.7 (1.4–9.7)0.008
Tacrolimus (vs. CsA)2.6 (1.32–5.30)0.0062.6 (1.3–5.5)0.009
Hepatitis C antibody positive3.2 (0.99–10.47)0.0533.4 (1.02–11.2)0.047
Rejection episodeb1.3 (0.7–2.6)0.452.0 (1.1–4.9)0.024
Polycystic kidney disease1.7 (0.69–3.95)0.26 
Body mass index at transplant >301.5 (0.63–3.30)0.38 
Transplant after 19983.0 (1.43–6.43)0.004 
Azathioprine (vs. mycophenolate mofetil)0.4 (0.18–0.92)0.031 
Induction therapy2.1 (1.09–4.08)0.026 
Serum creatinine >400 μmol/L at day 72.1 (0.96–4.60)0.063 
Oliguria (<1 L/24 h)1.4 (0.49–3.93)0.53 
Dialysis requirement 1st week post-transplant1.5 (0.63–3.62)0.36 
Male gender1.3 (0.63–2.48)0.53 
Pre-transplant dialysis2.3 (0.72–7.60)0.16 
Hypertensionb,c1.6 (0.38–6.57)0.53 
CMV mismatch (D+R−)0.6 (0.22–1.74)0.36 
Prednisone therapy post-transplantb1.01 (0.98–1.05)0.44 

As a marker of slow graft function or delayed graft function, induction therapy was associated with PTDM (2.1 (1.1–4.1); p = 0.03). However, dialysis requirement in the 1st week post-transplant was not. Hepatitis C antibody status met borderline significance (p = 0.053). Other variables such as recipient gender, hypertension, CMV mismatch, polycystic kidney disease and pre-transplant dialysis, were not associated with the development of PTDM.

Given that it is difficult to separate the effects of immunosuppression from the time of transplantation, our multivariate analysis demonstrated five clinical factors as having an independent association with developing diabetes following kidney transplantation (Table 2). The older recipient age increased the risk of becoming diabetic following kidney transplant by 1.5-fold for every 10-year increase in age (Table 2, Figure 2). Similarly, PTDM developed more commonly after deceased donor kidney transplantation (HR = 3.6, p < 0.01), than in recipients who received a kidney transplant from a living donor. For patients receiving tacrolimus, the proportion who developed PTDM was significantly higher than patients receiving cyclosporine (HR = 2.6, p < 0.01). An association was observed between PTDM and positive hepatitis C antibody status at time of transplant (HR 3.4 (1.02–11.02); p = 0.05) and having a rejection episode (HR 2.0 (1.1–4.9); p = 0.02).

image

Figure 2. Increasing age and PTDM.

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Prednisone therapy (either dose at different time points post-transplant or cmulative dose) was not associated with developing PTDM; however almost all of our recipients (97.4%) receive higher dose prednisone (0.1–0.5 mg/kg/day) for the first 6 months to a year post-transplant and are then maintained on lower doses or prednisone is withdrawn (Table 3). Furthermore, given that the majority of our patients are treated with prednisone post-transplantation, we did not observe a difference in use of prednisone or a cmulative dose effect between patients who developed PTDM as compared to those who did not. Furthermore, we examined the relationship between PTDM and calcineurin inhibitor dose and trough levels (Table 3). There was no association between trough levels of tacrolimus or cyclosporine at any time point following transplantation and development of diabetes. It is recognized that trough monitoring may not be the ideal surrogate marker of calcineurin inhibitor exposure as compared to abbreviated area under the curve (AUC) or peak monitoring. Peak monitoring was not analyzed as our center was not performing peak monitoring during this time period.

Table 3.  Comparisons of daily prednisone dose and calcineurin inhibitor 12-h trough levels between patients with PTDM and without PTDM (all non-significant)
 Mean ± S.D. (n)
PTDM (n = 38)No PTDM (n = 348)
  1. aNeoral cyclosporine; bNo mean reported as only two subjects in this group.

Prednisone daily dose (mg/day)
 3 months10.2 ± 8.0 (n = 38)10.9 ± 8.2 (n = 332)
 1 year6.0 ± 5.8 (n = 35)6.0 ± 3.9 (n = 315)
 2 years4.4 ± 2.4 (n = 27)5.2 ± 3.5 (n = 255)
Prednisone cmulative dose (mg)
 3 months1611 ± 635 (n = 38)1590 ± 704 (n = 332)
 1 year4474 ± 2828 (n = 35)4554 ± 2889 (n = 315)
 2 years7416 ± 4061 (n = 27)7038 ± 3702 (n = 255)
aCyclosporine trough (mmol/L)
 1 month328.8 ± 81.1 (n = 21)338.8 ± 94.2 (n = 240)
 6 months231.9 ± 72.7 (n = 22)217.0 ± 77.2 (n = 204)
 1 year193.1 ± 84.4 (n = 20)170.1 ± 57.1 (n = 189)
 5 years115.0 ± 46.7 (n = 6)113.6 ± 36.7 (n = 76)
Tacrolimus trough (mmol/L)
 1 month14.7 ± 3.4 (n = 15)13.1 ± 4.3 (n = 80)
 6 months9.5 ± 2.8 (n = 13)10.4 ± 3.5 (n = 116)
 1 year7.4 ± 2.8 (n = 14)9.1 ± 3.9 (n = 120)
 5 years(n = 2)b6.5 ± 2.4 (n = 28)

A BMI greater than 30 (defined obesity) at transplantation was not associated with developing diabetes after transplantation (Table 4; p = 0.38). However, as shown in Figure 3, the incidence of PTDM does increase with rising BMI (at transplant), although this did not reach statistical significance. There was no significant difference in weight or BMI at transplant or 6 months following transplant between the recipients who developed PTDM as compared to those who did not (Table 4). Finally, the change in BMI between time of transplantation and 6 months post-transplant was not associated with developing PTDM (p = 0.89), with only 9.6% of patients increasing their BMI by 1.5 to 3 points between the time of transplantation and 6 months thereafter.

Table 4.  Body mass index at transplant and 6 months post-transplant (all non-significant)
 Mean ± S.D.
PTDM (n = 38)No PTDM (n = 348)
Weight at
 Transplant75.7 ± 14.871.2 ± 18.8
 6 months post-transplant78.6 ± 15.374.7 ± 19.2
Body mass index at
 Transplant26.4 ± 4.525.3 ± 5.5
 6 months post-transplant27.4 ± 5.126.5 ± 5.6
image

Figure 3. Body mass index and PTDM.

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Overall, we did not observe PTDM to be associated with worse graft (Figure 4) and/or patient survival. In addition, there were no differences in renal function (serum creatinine or calculated creatinine clearance) at any time point post-transplant for patients who developed PTDM as compared to patients who did not (data not shown).

image

Figure 4. Graft survival and PTDM.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

We found a high overall incidence rate of 9.8% of de novo diabetes following kidney transplantation in our single center Canadian cohort study. A logical limitation of any study examining PTDM is under diagnosis. In our study, this is far less likely due to frequency and comprehensiveness of follow-up. In addition, although we examined a relatively large and detailed cohort of patients, limitations of retrospective studies exist and could result in our study being underpowered to determine other factors contributing to PTDM in this patient population.

Previous work has employed various definitions of PTDM and this has created some variability in the reporting of incidence rates and risk factors. We ensured accuracy of diagnosis and accounted for all cases of PTDM by confirming the diagnosis in two ways: by serum blood glucose levels as well as by treatment with oral hypoglycemic agents and/or insulin therapy. Patients who developed PTDM had blood glucose levels which met the Canadian Diabetes Association definitions for a diagnosis of diabetes mellitus (which are similar to the WHO guidelines) and were distinctly higher than patients who did not develop diabetes following transplantation. Our incidence rates, although high, are lower than previous studies assessing different demographic populations, such as the United States (2). This is likely due to a lack of racial predisposition and shorter follow-up time, but also may be due to demographic differences in BMI, post-transplant surveillance and care, and potentially because PTDM may confer a higher cardiovascular risk in non-Caucasian patients as demonstrated by decreased patient survival in studies in the US population. Similar to our observations, a European study has shown lower rates of PTDM in a primarily Caucasian kidney transplant population (21).

Five major clinical variables were associated with developing PTDM in our analysis: older recipient age; deceased donor, hepatitis C antibody status, rejection episodes and use of tacrolimus. Older age has consistently been shown to be an important risk factor for PTDM (1,6,7,15). For example, Cosio et al. examined 2078 non-diabetic renal transplant recipients treated with cyclosporine and prednisone, in a single center in the US and found recipient age over 45 years to be associated with a 2-fold increased risk of developing PTDM (p < 0.0001). We have also observed a similar relationship between age and PTDM (HR 1.5 (1.1–1.9); 0.006). Furthermore, there is an increasing trend in the general population of increasing rates of de novo diabetes, with increasing age (Diabetes in Canada: National Statistics and Opportunities for Improved Surveillance, Prevention and Control. Health Canada, 1999).

We confirmed that the choice of calcineurin inhibitor was associated with developing PTDM as previously reported. However the risk of PTDM associated with tacrolimus was independent of the actual exposure level of tacrolimus and this is a new finding. Further evidence to support this finding derives from a study by Hricik et al. of 56 African American adult, primary kidney transplant recipients treated with corticosteroids, sirolimus, and tacrolimus targeted to relatively low trough blood levels who were compared to a concurrent group of 65 white patients treated with steroids, mycophenolate mofetil, and tacrolimus targeted to relatively high blood levels (22). The authors found that PTDM occurred in 36% of the African American patients, despite similar doses of corticosteroids and lower trough levels of tacrolimus, compared to 15% of white patients (p = 0.02). Thus, PTDM was a major problem for African Americans receiving this combination of immunosuppressants, despite relatively low tacrolimus exposure.

Deceased donors were associated with increased development of PTDM and other studies have shown a similar relationship (2,6,9). The explanation for this relationship may be postulated to be related to differences between deceased and living donor transplantation including older recipient age, more immunosuppression (i.e. induction therapy, higher levels of calcineurin inhibitor, higher steroid doses), use of tacrolimus preferentially in deceased donor transplant recipients and more delayed graft function. However, further analysis of our population did not reveal any of these to be legitimate explanations. In particular, the dose of steroid, the mean levels of calcineurin inhibitor, the use of tacrolimus did not differ by donor type. Furthermore, deceased donor recipients were older. However, age and deceased donor type were independent of each other in their association with PTDM. Induction therapy was used more frequently in deceased donor transplantation. However, further analysis of interaction did not explain this finding. Thus, we lack a clear biologic explanation for the increased risk conveyed by deceased donor transplant for developing PTDM; nevertheless, it is reasonable to assume that individuals without a potential living donor should be identified as higher risk for developing PTDM during the transplant work-up process and should be educated and cautiously monitored and managed.

The lack of association of BMI with development of PTDM differs from previous studies. However, we do have a lower proportion of patients with significant obesity (BMI ≥ 30; 14.3%) as compared to other studies (2) that have shown an association of obesity with PTDM. In fact, 50% of our patient population entered transplantation with a normal BMI (<25). Notably, the proportion of patients who actually increased their BMI over a 6-month period post-transplant was low (∼10%).

Kasiske et al. have shown that hepatitis C antibody status is associated with developing PTDM (2,23). In our study, hepatitis C antibody status was borderline significant in univariate analysis (p = 0.05) and demonstrated significance in multivariate analysis (p = 0.04). Given that successful antiviral treatment of hepatitis C in liver transplant recipients appears to be associated with improved glycemic control (24,25), it is possible that successful pre- or post-transplant treatment of hepatitis C could potentially reduce the incidence of PTDM after renal transplantation as well.

The lack of relationship between maintenance corticosteroid use and PTDM is somewhat unexpected. However, our prevalent use of corticosteroid post-transplantation prohibits an adequate comparision with a group of recipients not on prednisone, and therefore it is difficult to draw any major conclusions. Furthermore, the fact that having a rejection episode (and therefore treatment with high dose solumedrol) was independently associated with PTDM may be a result of the inherent nature of relationship between corticosteroids and hyperglycemia. In other words, short term high dose steroid exposure precipitates hyperglycemia and increases the risk of developing PTDM.

Although we did not find PTDM to worsen graft or patient survival in our study, larger studies (2) have shown a detrimental relationship with graft survival. This likely occurs secondary to the effects of concomitant hypertension and minimization of steroid once the diagnosis of PTDM is made (26), as well as with patient survival, which is worsened because of an increased incidence of infections (27,28) and cardiovascular disease.

In summary, this study shows that in a Canadian kidney transplant population that there is a significant risk of PTDM following the transplant. Identifiable risk factors include: age, deceased donor, tacrolimus use, hepatitis C antibody status and rejection episodes (exposure to high dose steroid). Given that PTDM has been shown to reduce graft and patient survival in some datasets, it seems reasonable to consider strategies to reduce the risk of PTDM. Lifestyle modification to reduce the risk of PTDM is an important strategy which should be emphasized. The dilemma remains as to what strategy will best reduce the composite risk of the transplant recipient which includes PTDM, rejection, hypertension, dyslipidemia, cosmetic side effects, renal function and graft and patient outcomes. Thus it is difficult to recommend the selection of a specific immunosuppressive regimen, such as one CNI as compared to the other, or steroid minimization as compared to elimination and whether tailoring of immunosuppression should be part of risk factor modification remains unknown. PTDM is a significant complication of renal transplantation. However, it is only one element of many that affect graft and patient outcome and should be considered as part of the broad picture of the total risks faced by the kidney transplant recipient.

Acknowledgment

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References

We would like to acknowledge Mrs. Susan Huygen for her contribution to this manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgment
  8. References
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