Tapering off prednisolone and cyclosporin the first year after renal transplantation: the effect on glucose tolerance

Jøran Hjelmesæth,1, Anders Hartmann1, Johan Kofstad2, Thore Egeland3, Jean Stenstrøm1 and Per Fauchald1

1 Department of Medicine, 2 Department of Clinical Chemistry and 3 Center of Clinical Epidemiology, National Hospital, University of Oslo, Oslo, Norway



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. Glucose intolerance is an untoward side effect of some immunosuppressive and anti-hypertensive drugs. The primary aim of the present prospective observational study was to test the hypothesis that tapering off prednisolone and cyclosporin (CsA) the first year after transplantation may have beneficial effects on glucose tolerance in renal transplant recipients.

Methods. Ninety-one non-diabetic recipients were included, and 87 patients underwent a 75 g oral glucose tolerance test both 10 weeks and 1 year after renal transplantation. The change over time in 2-h blood glucose was compared with a number of variables potentially influencing glucose tolerance.

Results. The proportion of glucose intolerant recipients was reduced from 55 to 34% during the study. Univariate linear regression analysis showed a significant association between the reduction in daily prednisolone dose down to 5 mg and decline in blood glucose (P=0.001), whereas weight gain was associated with increasing blood glucose (P=0.031). Each 1-mg reduction of prednisolone dose leads to an estimated decline in 2-h blood glucose of 0.12 mmol/l based on the multiple linear regression model (P=0.003). Twelve out of 22 patients with post-transplant diabetes mellitus (PTDM) at baseline improved to normal or impaired glucose tolerance. Ten PTDM-subjects who remained diabetic 1 year after transplantation had lower serum insulin levels during the oral glucose challenge, and five patients treated with anti-diabetic drugs at baseline required hypoglycaemic drugs also at follow up. The decline in CsA level of 100 µg/l and the lower number of patients treated with beta-blockers at follow-up, did not alter glucose tolerance significantly.

Conclusions. Tapering off prednisolone, but not CsA, significantly improves glucose tolerance during the first year after renal transplantation.

Keywords: anti-hypertensive drugs; cyclosporin A; post-transplant diabetes mellitus; post-transplant glucose intolerance; prednisolone; renal transplantation



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Glucose intolerance, including post-transplant diabetes mellitus (PTDM) and impaired glucose tolerance (IGT), is a common feature after renal transplantation [1,2]. There is some evidence that PTDM leads to an increased risk for subsequent infectious [3,4] and cardiovascular complications [5,6]. Furthermore, both reduced patient and graft survival have been reported as complications to PTDM [79], the latter possibly in part caused by allograft diabetic nephropathy [10].

Immunosuppressive therapy provokes glucose intolerance, prednisolone by increasing insulin resistance, whereas the mechanisms for the diabetogenic effect of cyclosporin (CsA) and tacrolimus are less well defined [1,2,11]. It is well known that steroid withdrawal has beneficial effects on PTDM [1,12,13], but to our knowledge the influence of a dose reduction of prednisolone or CsA on glucose tolerance has not been investigated.

Anti-hypertensive drugs may also alter glucose tolerance, and in a recently published 6-year follow-up cohort study including 12 550 people, the use of beta-blockers significantly increased the risk for type 2 diabetes [14]. We have previously reported that the use of beta-blockers is associated with IGT in renal transplant recipients [2].

The present study was designed primarily to test the hypothesis that tapering off prednisolone and CsA improves glucose tolerance during the first year after renal transplantation in recipients on triple drug therapy. Secondary aims were to assess the potential effect of changes in body weight, kidney function and anti-hypertensive therapy, and to evaluate any prognostic impact of serum insulin at baseline on changes in glucose tolerance during the first year after transplantation.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Study population
Between May 1995 and April 1996, 109 consecutive non-diabetic renal transplant recipients were evaluated for inclusion. The series comprises a follow up of the first two-thirds of the patients enrolled in a published study of 173 renal transplant recipients [2]. Twelve patients declined to participate in the follow-up assessment, two patients died and four recipients were treated with tacrolimus, leaving 91 recipients for inclusion in the present prospective observational study. All patients gave informed consent to participate, and the study was performed in accordance with the Declaration of Helsinki [15].

The primary renal disease was glomerulonephritis in 42% of the recipients, 15% had polycystic kidney disease, 15% pyelonephritis and 13% had nephrosclerosis with no significant differences between the categories of patients with varying degrees of glucose tolerance.

Oral glucose tolerance test (OGTT)
With the exception of two recipients with manifest PTDM, all patients completed a 75 g OGTT at the National Hospital 10 weeks post-transplant (baseline). Venous blood samples were taken before, 1- and 2-h after the glucose load for immediate analysis of serum glucose, and serum was frozen for analysis of insulin. The recipients were divided into three different categories of glucose tolerance according to the WHO criteria [16]; PTDM with fasting serum glucose above 7.7 mmol/l (>=7.8) or 2-h serum glucose above 11.0 mmol/l (>=11.1); IGT with fasting glucose less than 7.8 mmol/l and 2-h glucose between 7.8 and 11.1 mmol/l; and normal glucose tolerance (NGT) with both fasting and 2-h serum glucose less than 7.8 mmol/l.

At a median of 13 months (range 11–20) after transplantation a 75-g OGTT was repeated in 89 patients including measurement of fasting and 2-h blood glucose. Two of the five patients with PTDM who still were on hypoglycaemic therapy did not undergo the OGTT at follow-up.

Eighty-seven patients underwent both OGTTs. Twenty-six patients were examined at our centre and 65 at their local nephrological centre.

Analytical procedures
At baseline, the analysis of serum glucose was performed using a glucose dehydrogenase method (Cobas Mira, Roche, Switzerland). At follow-up, venous serum glucose was measured in 73 patients and capillary whole-blood glucose in 18 patients. Serum insulin was determined by a commercial radioimmunoassay (Coat-A-Count®, Diagnostic Products Corporation, Los Angeles, CA, USA). Whole blood CsA concentrations were measured using a CsA-specific fluorescence polarization immunoassay (TDx analyzer, Abbott Laboratories, Chicago, IL, USA). At follow-up, analyses of glucose and serum creatinine were performed as part of the normal clinical routines. Creatinine clearance was calculated from the Cockcroft and Gault formula [17].

Questionnaire
The nephrologists completed a questionnaire with the results of blood tests, patient weight, and present medication including hypoglycaemic agents, antihypertensives, diuretics, and immunosuppressive drugs.

Immunosuppressive therapy
Ten weeks after transplantation, all patients (n=91) were treated with prednisolone and CsA (Sandimmun Neoral®), and 87% with azathioprine. During the study two patients stopped treatment with CsA, one was converted to tacrolimus and one patient underwent graftectomy. Details on the early post-transplant immunosuppressive protocol and the diagnosis and treatment of rejections have been published elsewhere [2]. National guidelines recommend a maintenance dose of 10 mg of prednisolone until 1 year after transplantation with optional tapering to 5 mg during the second year. The prescription of CsA is adjusted to keep trough whole blood CsA concentration between 100 and 150 µg/l following the first 3 months after transplantation. Azathioprine is given in a maintenance dose of 1 mg/kg/day.

Statistical analysis
One-way analysis of variance was used in the analysis of continuous data, and Pearson {chi}2 test for categorical data when comparing the different categories of glucose tolerance at 10 weeks after transplantation (baseline). For sparse tables, {chi}2 statistics were based on Monte-Carlo simulations in Statxact. Paired t-test (continuous data) or McNemar's test (categorical data) was used to evaluate differences between baseline and follow-up. Skewed data were log transformed before statistical analysis (serum insulin). The difference in 2-h blood glucose was used as the dependent variable and potential predictors of changes in glucose tolerance as independent variables in a linear regression model. Multiple linear regression was used to define any independent predictors of change in glucose tolerance. Two-tailed P-values are reported, and values below 0.05 considered significant. The analysis was implemented using SPSS [18].



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Patient characteristics 10 weeks after transplantation (baseline) are shown in Table 1Go. Twenty-two recipients (24%) had PTDM, 28 (31%) IGT, and 41 (45%) NGT. Glucose intolerant recipients were older, used higher doses of prednisolone, more often received a cadaveric kidney, and were more frequently on beta-blocker therapy than patients with NGT. There were no statistically significant differences between the groups regarding the family history of diabetes, gender, body mass index (BMI), creatinine clearance, whole blood CsA trough concentration, and the number of patients using anti-hypertensive drugs.


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Table 1. Patient characteristics at 10 weeks post-transplant (baseline)

 
Baseline glucose and insulin parameters are shown in Table 2Go. Mean serum fasting insulin was not statistically different between the groups, whereas the 1-h insulin level increased with improving degree of glucose tolerance, and the 2-h insulin level was higher in the patients with IGT than in those with PTDM or NGT.


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Table 2. Serum glucose and insulin at baseline

 
Follow-up data for all patients at one year are given in Table 3Go. There was a statistically significant decline in mean fasting blood glucose (0.5 mmol/l, P=0.007) and 2-h blood glucose (1.6 mmol/l, P<0.001). The daily oral prednisolone dose was reduced by a mean of 6.0 mg (range +10 to –30 mg, P<0.001). Fifty-two patients were treated with prednisolone 10 mg/day, whereas 37 patients used a prednisolone dose between 5 and 8.75 mg/day 1 year after transplantation.


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Table 3. Changes in glucose parameters, immunosuppressive therapy, weight, renal function, and anti-hypertensive medication during the first year after transplantation

 
The mean dose reduction of prednisolone was most pronounced in patients with early PTDM (8.7 mg, P<0.001) and IGT (7.2 mg, P<0.001), with a corresponding decline in the 2-h blood glucose of 4.2 mmol/l (P<0.001) and 1.4 mmol/l (P=0.017), respectively. On the other hand, a mean dose reduction of prednisolone of 3.7 mg (P<0.001) and decline in the 2-h blood glucose of 0.7 mmol/l (P=0.002) was observed in the NGT-group. A significantly greater reduction in the daily prednisolone dose was observed in patients with PTDM and IGT compared with the NGT-patients (unpaired t-test, P=0.006 and 0.030, respectively).

Whole blood CsA concentration, creatinine, and the numbers of patients treated with beta-blockers were significantly lower than at baseline, whereas BMI and creatinine clearance increased significantly 1 year after transplantation (Table 3Go).

When the difference in 2-h blood glucose (Y) was considered being the dependent variable, univariate linear regression analysis showed a significant association between reduction in prednisolone dose (X1) and improvement in glucose tolerance (Y=-0.89+0.13 X1, r2=0.12, P=0.001). On the other hand an increasing BMI (X2) was associated with worsening of glucose tolerance (Y=–2.12+0.35 X2, r2=0.05, P=0.031). Age, anti-hypertensive medication and treatment with beta-blockers or diuretics at baseline, did not influence glucose tolerance significantly in the linear regression analysis model. Changes in the number of patients using beta-blockers, CsA trough concentration or renal function, were not associated with altered glucose tolerance.

After including the change in prednisolone dose and BMI in a multiple linear regression model, the association between prednisolone dose reduction and decline in 2-h blood glucose remained significant (P=0.003), whereas the negative association with BMI was weakened (P=0.085). Each 1 mg dose reduction of daily prednisolone leads to an estimated decline in 2-h blood glucose of 0.12 mmol/l based on the multiple regression model (R2=0.15).

Six patients with PTDM at baseline improved to NGT, six improved to IGT and 10 patients remained diabetic 1 year after transplantation (Figure 1Go). The majority (37 of 41) of patients with NGT at baseline remained normoglycaemic at follow-up. Four of the 28 patients with IGT at baseline progressed to PTDM, whereas 17 improved to NGT. The proportion of glucose intolerant (PTDM and IGT) recipients was reduced from 55 to 34% during the study.



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Fig. 1. Changes in glucose tolerance category from early (10 weeks) to late (1 year) after renal transplantation. PTDM, post-transplant diabetes mellitus; IGT, impaired glucose tolerance; NGT, normal glucose tolerance.

 
Three of the four patients who progressed from IGT to PTDM gained between 8 and 17 kg in body weight, of whom two reported a positive family history of diabetes. Furthermore two of these patients did not reduce the prednisolone dose during the study (10 mg/day).

The PTDM-subjects who remained diabetic at follow-up (n=10) had a lower-fasting insulin (P=0.121, unpaired t-test) and both a significantly lower 1-h insulin (P=0.005) and 2-h insulin (P<0.001), than the diabetics who improved one or two glucose tolerance categories (n=12) (Figure 2Go). The five patients treated with insulin or oral hypoglycaemic agents at baseline were on hypoglycaemic medical therapy also at follow-up.



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Fig. 2. Mean (SD) serum insulin concentrations during a 75-g OGTT 10 weeks after transplantation in patients with PTDM. The 10 subjects who remained diabetic 1 year after transplantation are shown in open bars. The 12 patients who were classified as non-diabetic after 1 year are shown in black bars. The statistical analysis of differences between groups was performed after log transformation of data. *P=0.121, **P=0.005, ***P<0.001.

 



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
It is well established that treatment with glucocorticoids induces insulin resistance. Suggested mechanisms are impaired endothelium-dependent vasodilatation, decreased insulin receptor number and affinity, increased lipolysis and circulating free fatty acids, impaired glucose uptake by muscle, and reduced glycogen synthesis [19,20]. In animal models glucocorticoids counteract the insulin effect on the rate-limiting enzyme in the gluconeogenesis, phosphoenol-pyruvate carboxykinase [19], and glucocorticoid treatment inhibits glucose-induced insulin release from pancreatic beta-cells [19,21].

It has been argued that the diabetogenic effects of steroids may be dose dependent [22]. However, the present prospective observational study is to our knowledge the first to show that dose reduction of oral prednisolone significantly improves glucose tolerance during the first year after renal transplantation. An independent linear association was found between the reduction in daily oral prednisolone dose and the corresponding decline in 2-h blood glucose.

The effect of prednisolone tapering was most pronounced in the patients with PTDM at baseline; less than half were diabetic after 1 year. The PTDM subjects who remained diabetic at follow up had lower serum insulin levels during the OGTT at baseline as compared with the patients who improved to IGT or NGT (Figure 2Go). Furthermore, all recipients treated with glucose lowering drugs at baseline (n=5) were still on hypoglycaemic medication at follow-up. This implies that early need for hypoglycaemic therapy and impaired insulin secretion represent negative prognostic factors with respect to improvement in glucose tolerance after renal transplantation.

Although not surprising, it is noteworthy that the majority of patients with NGT at baseline remained euglycaemic at follow up, and no one developed PTDM after 1 year. On the other hand four out of 28 IGT-patients progressed to PTDM. Thus IGT early after renal transplantation may represent a risk factor for the development of subsequent PTDM, which is in accordance with findings in the general population [23].

The mean serum 1-h insulin was lower in PTDM subjects as compared with individuals with IGT or NGT. This is consistent with the findings of previous studies [24,25]. Our results underscore the importance of an insufficient pancreatic insulin response in recipients with PTDM supporting the view that the pathogenesis of PTDM is similar to that of type 2 diabetes [26].

The use of corticosteroids is associated with numerous side effects including glucose intolerance, hypertension, dyslipidemia, osteopenia, and infections. Steroid-sparing immunosuppressive protocols may therefore lead to a reduction in both patient morbidity and mortality [27].

Steroid withdrawal has been reported to improve metabolic disturbances in recipients with PTDM [12]. Increased rate of rejections [12] or declining graft function [28] are, however, serious untoward effects of steroid cessation. The introduction of more potent and less diabetogenic immunosuppressive agents such as anti-interleukin-2 receptor monoclonal antibodies, sirolimus, and mycophenolate mofetil may, however, facilitate the use of low-dose steroid or steroid-free immunosuppressive regimens in the future [29]. In a very recently published study, seven consecutive patients with type 1 diabetes were successfully transplanted with pancreatic islet cells on a glucocorticoid-free immunosuppressive protocol that included sirolimus, low-dose tacrolimus, and daclizumab [30].

Patients remaining diabetic despite tapering off prednisolone may have benefited particularly from the withdrawal of steroids. It is conceivable that a dose reduction of prednisolone below 5 mg/day may have an additional benefit on glucose tolerance, but this could not be assessed in the present study.

Glucose tolerance was not influenced by a marked reduction in trough whole blood CsA during the first year after transplantation. Although the diabetogenic effects of CsA have been questioned [1,31], both animal studies [32] and the increased incidence of PTDM after the introduction of CsA strongly indicate a negative effect on glucose tolerance [1]. Both increased insulin resistance and toxic effects on pancreatic islet cells have been suggested as mechanisms [1,32]. The combination of prednisolone and CsA may also be deleterious because of mutual inhibition of metabolism [33]. Our results do neither support nor rule out a possible diabetogenic effect of CsA but indicate that any such effect cannot be strictly dose dependent.

The introduction of tacrolimus was expected to reduce the incidence of PTDM because of its steroid sparing effects. However, in a meta-analysis of four randomized trials including 1037 patients, treatment with tacrolimus was associated with a 5-fold increased prevalence of diabetes mellitus after transplantation compared with treatment with CsA [11]. The diabetogenic effect of tacrolimus may be dose related [22].

In a recently published, large prospective cohort study beta-blockers were the only anti-hypertensive drugs associated with development of type 2 diabetes [14]. Even though the number of patients using beta-blockers in the present study was reduced by nearly one-third from baseline to follow up, we could not demonstrate any significant improvement in glucose tolerance. Furthermore, the use of beta-blockers at baseline was not associated with a worsening in glucose tolerance. A larger prospective study of longer duration may, however, be necessary to answer the question whether cessation of beta-blocker therapy is associated with improved glucose tolerance in renal transplant recipients.

It is well known that weight gain and physical inactivity induce insulin resistance and glucose intolerance [26]. During the study period our patients gained on average more than 4 kg in body weight, but most of them were not obese neither at baseline (mean BMI=23.6 kg/m2) nor at follow-up (mean BMI=25.0 kg/m2). In the univariate linear model weight gain was associated with worsening of glucose tolerance, but the association was weakened when steroid dose reduction was included in the multiple linear model. Nevertheless weight reduction may be an important therapeutic approach in overweight patients. Physical activity level in relation to glucose tolerance was not assessed in the present study.

Renal failure is associated with worsening of glucose tolerance [34]. However, the small improvement in renal function was not significantly associated with improved glucose tolerance in the present study.

In the present study the 1985 WHO criteria for the diagnosis of glucose intolerance were used. After implementation of the new diagnostic criteria [35], only one patient changed from IGT to PTDM and two patients changed from NGT to impaired fasting glucose. The principal findings of our study were not altered.

Other factors known to influence glucose tolerance may be of importance even not revealed in the present study. The limited number of patients included and the rather short duration of our study should lead to some caution in the interpretation of the results at least until they are confirmed by others.

In conclusion, tapering off prednisolone but not CsA, significantly improves glucose tolerance during the first year after renal transplantation. PTDM-patients with an impaired insulin response after an oral glucose challenge and patients on glucose lowering medication had less benefit of prednisolone dose reduction. A dose reduction of prednisolone below 5 mg/day may further improve glucose tolerance, but could not be assessed in the present study.



   Acknowledgments
 
The authors thank colleagues at 19 local nephrological centres in Norway for supplying data to the follow-up study.



   Notes
 
Correspondence and offprint requests to: Jøran Hjelmesæth, Medical Department, Vestfold Central Hospital, Boks 2168, N-3103 Tønsberg, Norway. Back



   References
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 30. 5.00
Revision received 7.11.00.