1 Department of Nephrology and 2 Department of Biochemistry, Christian Medical College Hospital, Vellore, India
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Abstract |
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Methods. Non-diabetic adult end-stage renal failure patients awaiting renal transplantation were studied prospectively. Their nutritional status was assessed as body mass index (BMI), serum albumin, and the evolution of these parameters over time prior to transplantation. An oral glucose tolerance test (OGTT) was performed pre- and serially post-transplant until 6 months. Pre- and post-transplant risk factors such as age, nutritional status, glucose tolerance parameters and immunosuppression were related to the development of PTDM or impaired glucose tolerance (IGT) post-transplant.
Results. The mean age of 174 patients studied over a 2-year period was 32.9±9.7 years. The mean post-transplant follow-up was 25.6±12.8 months. The mean BMI at recruitment was 18.3±2.4 kg/m2. The rate of increase in BMI pre-transplant showed an inverse correlation with the baseline BMI (r=-0.34, P=0.000) and formed an independent marker of nutritional status. PTDM developed in 21.4% patients and 24.1% had IGT. On univariate and multivariate analyses, the factors significantly associated with the development of PTDM were greater age, more rapid increase in dry weight after starting haemodialysis (HD), elevated pre-transplant OGTT responses and cyclosporin (CsA) and prednisolone doses early post-transplant. Additionally, on multivariate analysis, higher CsA trough level >300 ng/ml at 3 months increased the risk for the development of PTDM. Of patients who developed PTDM, 57% had impairment of glucose tolerance pre-transplant (>140 mg/dl at 2 h). Patients with a 1-h glucose value greater than the 50th percentile on pre-transplant OGTT had a 3.9-fold greater risk for the development of PTDM (P=0.05, 95% CI=1.0311.1). In those patients with higher 1-h glucose (>50th percentile) who also gained in dry weight rapidly pre-transplant, the risk increased to 5.3 (P=0.02). Of 76 patients with abnormal OGTT early post-transplant, only 68% continued to have PTDM or IGT post-transplant, the remainder reverting to normal glucose tolerance.
Conclusions. Persistent abnormal glucose tolerance after transplantation was seen in 45% of the patients. Pre-transplant factors including greater age, abnormal glucose tolerance parameters, and rapid gain in dry weight on HD, along with higher prednisolone and CsA doses early post-transplant were the important factors associated with the development of PTDM. Identification of patients with pre-transplant risks might allow modification of post-transplant immunosuppression with non-diabetogenic agents.
Keywords: body mass index; cyclosporin; malnutrition; oral glucose tolerance test; post-transplant diabetes mellitus; prednisolone
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Introduction |
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Populations with a high background prevalence of diabetes appear to have an increased incidence of PTDM [3,4]. Non-insulin-dependent diabetes mellitus (NIDDM) is common in India [5] and in Indian immigrants to Western societies [6]. The latter observation has highlighted the link with the thrifty phenotype, and the possible role of malnutrition in the pathogenesis of NIDDM [7,8]. Early-life malnutrition coupled with over-nutrition later in life might play a role in the pathogenesis of NIDDM [9]. As a corollary, malnutrition, common in haemodialysis (HD) patients [10,11] may contribute to the pathogenesis of PTDM in a phenotypically predisposed population [5], and its role as a risk factor for the development of PTDM has not been addressed before.
This study was conducted to identify the pre- and post-transplant risk factors for the development of PTDM, with special emphasis on pre-transplant nutritional status, glucose tolerance parameters and immunosuppression.
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Subjects and methods |
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Patient details collected included age, sex, height, weight, donor source (live related or cadaver) and transplant type (pre-emptive or following a period on regular thrice-weekly HD). Pre-transplant nutritional status was measured as dry weight, body mass index (BMI, calculated as weight/height2) and serum albumin, serially at monthly intervals, until the patient underwent transplantation. All assessments were performed when the patient was clinically stable. Using the classification of Ferro Luzzi et al. [14], the severity of malnutrition was graded according to the absolute levels of BMI. From the serial values of BMI during the pre-transplant period, the slope of increase in BMI over time was calculated for each patient (summary statistic) [15]. Prednisolone and CsA doses per kilogram body weight in the first week of every month were recorded. CsA trough levels were measured using the EMIT assay [16].
An oral glucose tolerance test (OGTT) was performed pre- and post-transplant at 2 weeks, 6 weeks, 3 months and 6 months, except in those with any acute systemic illness or on steroid therapy in the pre-transplant period. Plasma glucose was measured immediately before and at 1, 2 and 3 h after a 75 g oral glucose load. Patients who developed overt diabetes after transplantation based on OGTT or on symptoms were subsequently monitored with fasting and 2-h post-prandial blood glucose estimation.
Based on the results of the post-transplant OGTTs and using the American Diabetes Association criteria [17], patients were classified into those with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or overt diabetes (PTDM). Patients with a 2-h glucose value of >140 mg/dl on the pre-transplant OGTT were categorized as having impairment of glucose tolerance, but no further classification was employed in view of the background uraemic state.
The outcome variables were the development of PTDM alone or a composite outcome of either PTDM or IGT post-transplant. Their relationship to pre-transplant nutritional status and glucose tolerance parameters, and post-transplant immunosuppression was studied. In addition, the predictive value of abnormal glucose tolerance pre-transplant and the diagnostic value of the early post-transplant OGTT for the development of sustained post-transplant glucose intolerance or PTDM were evaluated.
Statistical analysis
All results were expressed as means±SD. The chi square test for proportions and linear trends, and the one-way ANOVA were used to analyse the differences between groups. The evolution of BMI over different time points in the different categories of glucose tolerance post-transplant was analysed using ANOVA for repeated measures. Since the distribution of CsA levels in the population did not follow a normal pattern, the KruskalWallis one-way ANOVA was used to study its relationship to the different categories of glucose tolerance. Logistic regression analysis was used to identify risk factors for the development of IGT and PTDM. Independent variables were divided into factors present pre- and post-transplant. The pre-transplant OGTT and post-transplant CsA levels were evaluated with receiver-operating characteristic (ROC) curves to identify possible threshold values for the development of PTDM.
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Results |
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The mean BMI of the cohort at recruitment was 18.3±2.4 kg/m2; 56% had a BMI <18.5 kg/m2. The slope of increase in BMI after instituting dialysis showed a low but significant inverse correlation to the level of BMI at the start of dialysis (r=-0.34, P=0.000).
Of the 174 patients, 38 (21.4%) developed PTDM, 74.4% within the first 3 months and 90% within the first post-transplant year. IGT after transplant was seen in 24.1% and 20.7% had a transient abnormality of glucose tolerance.
Tables 1 and 2
show univariate analyses relating various factors to IGT/PTDM. Greater age was significantly associated with PTDM. Although the initial and immediate pre-transplant BMIs were not significantly different, a higher rate of increase in BMI pre-transplant was noted in patients who developed PTDM. This difference was more marked when compared with patients who had NGT. However, after transplantation, PTDM patients did not gain weight significantly and their BMI at 6 months was significantly lower than in those who did not develop PTDM (Figure 1
). The evolution of BMI over time in the three outcome groups was significantly different; although PTDM patients showed a higher rate of increase in BMI pre-transplant, this did not carry over to the post-transplant period. The CsA concentrations at 3 months post-transplant were higher in patients who developed PTDM compared to those who had NGT. A significantly higher proportion of patients with pre-transplant impairment of glucose tolerance (2-h glucose values of >140 mg/dl) or those with first hour values greater than the median developed PTDM.
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Discussion |
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A doseresponse relationship for steroids has been demonstrated in some studies. Hjelmesaeth et al. [18] demonstrated that the risk of developing PTDM was 5% per 0.01 mg/kg/day of increase in prednisolone dose. The change from high-dose to low-dose steroids was associated with a decrease in the incidence of PTDM [22]. In the present study we again were able to demonstrate a relation to increasing steroid dose. As a fixed-dose protocol was used, this risk also represented the interaction of dose with body weighta higher steroid dose per kilogram body weight in those patients with lower body mass.
The CsA concentration at 3 months, on both univariate and multivariate analysis, significantly correlated with IGT and PTDM in this cohort. Every 100 ng/ml increase in the trough level increased the risk of developing either post-transplant IGT or PTDM by 50%. Higher CsA dose in the early post-transplant period was also a risk factor for the development of PTDM. A doseresponse relationship between CsA and PTDM has been shown in previous studies [21].
The role of body mass in relation to PTDM has been previously studied in overweight or obese subjects. Boudreaux et al. [23] found that patients who weighed >70 kg had a higher incidence of PTDM (21.1 vs 5.1%); Cosio et al. [3] documented a relative risk of 1.4 for developing PTDM for every 10 kg increase in body weight >60 kg. The role of malnutrition in ESRD patients in relation to PTDM has not been previously addressed. Malnutrition is one of the determinants of diabetes in tropical countries, having an indirect role in its pathogenesis [7]. It may unmask or amplify the effect of a primary diabetogenic influence that in itself may not be operating to its full extent [24]. Epidemiological studies have shown a strong association between early malnutrition and the risk of diabetes and syndrome X later in life [25,26]. The increased risk of diabetes is associated with fetal malnutrition [27]. On the one hand, impaired development of beta cells during a critical period of intra-uterine and early neonatal life results in an irreversible diminution in beta cell number and mass [25]. On the other hand, resistance develops to the actions of growth-promoting factors such as insulin and persists into post-natal life. The interaction of these two processes increases the susceptibility to the future development of diabetesthe thrifty phenotype hypothesis [28]. This hypothesis is relevant in the causation of diabetes in countries like India, where nearly a quarter of all babies born have low birth weight [29]. Early life malnutrition coupled with over-nutrition later in life suggests an ongoing interaction between the two ends of the spectrum of dysnutrition in the pathogenesis of adult diabetes [9]. A parallel can be drawn between this and patients with ESRD who are malnourished, who may gain weight rapidly as their uraemia is controlled on dialysis and subsequently after transplant compounded by the diabetogenic property of the current immunosuppressive drugs. In this study the identification of pre-transplant glucose intolerance as a risk factor in the presence of malnutrition is further support of this hypothesis, identifying a subgroup with pre-existing phenotypic predisposition.
Malnutrition at the start of dialysis was common in this cohort, with 80% of patients having a BMI less than the normal ranges for the Indian population [30]. The slope of increase in BMI prior to transplantation, although an indicator of nutritional recovery, also formed a surrogate marker for the severity of baseline nutritional impairment in these patients, showing a rough inverse correlation to the level of BMI at start of HD; thus a rapid increase in BMI pre-transplant, at these low ranges of BMI, would imply that a patient was more severely malnourished. BMI and its evolution over time on dialysis were two somatic markers of nutritional status used in this study. While there was no significant difference in the immediate pre-dialysis and immediate pre-transplant BMI between patients who developed PTDM and those who had NGT, a higher rate of increase in BMI pre-transplant was seen in PTDM patients. The association of weight gain to the development of diabetes mellitus is well known. Resnick et al. [31] showed that relative to overweight patients with stable weight, each kilogram of weight gained annually over 10 years is associated with a 49% increase in risk of developing diabetes in the subsequent 10 years. Weight gain appeared to have a similar significance in this study, but in the context of malnourished patients, as a manifestation of nutritional recovery, and could be perceived as a marker of the severity of undernutrition. The relative lack of weight gain post-transplant in those who developed PTDM may be explained by the diabetic state itself. Serum albumin, a visceral marker of nutritional status, did not show any relationship to the development of IGT.
IGT pre-transplant has been observed in several previous studies [2,32]. In this cohort, 57% of patients who developed PTDM and 53% of patients who developed post-transplant IGT had a 2-h glucose value >140 mg/dl on the pre-transplant OGTT. On the ROC curve, however, definite thresholds were not apparent for the 2-h glucose value, and false positives on the pre-transplant OGTT may be explained by the glucose intolerance of uraemia that corrects after transplantation [33]. The 1-h glucose value on pre-transplant OGTT testing gave better predictive value for the development of PTDM. Indeed it may be speculated that the 1-h glucose on the OGTT may be more representative of the impaired first-phase insulin secretion that is known to precede the development of overt diabetes in predisposed individuals [34].
Only a few studies have utilized a GTT to diagnose PTDM [18,21]. Using a single GTT at 10 weeks post-transplant to screen for PTDM in CsA treated patients, Hjelmesaeth et al. [18] documented PTDM in 18% and IGT in 31% of the patients. However, being a single GTT, this may have also identified patients who transiently developed impairment of glucose tolerance but did not develop PTDM over longer follow-up. This is demonstrated in the present study where a 31.6% false-positive rate was noted. The long-term implication of an early post-transplant abnormal GTT that does not evolve into PTDM is not known. Whether these patients will develop PTDM many years after transplantation is an unanswered question. Von Kiparski et al. [32] found that only 21.4% of patients who developed late-onset PTDM had an IGT pre-transplant as compared with 55.6% of early diabetics. In this cohort, very few patients developed late-onset PTDM and so this issue could not be addressed. In clinical practice, it may not be necessary to perform serial OGTTs after transplantation. However, an OGTT pre-transplant would help in identifying patients predisposed to the development of PTDM and these patients can be monitored more closely for the development of PTDM. The predictive value would be improved if interpreted in the context of other clinical risk factors that may be present.
In summary, the older patient with abnormal OGTT parameters pre-transplant is at higher risk of developing PTDM. This risk may be increased if the patient is malnourished and shows a rapid increase in weight pre-transplant once HD is initiated, showing the interplay between factors that may all be associated with a declining pancreatic beta cell reserve. Pre-transplant nutritional status thus has a discernible link to the development of PTDM. The basis of this link will be an interesting area for future study. Since immunosuppressive agents add to the risk, the practical implication of identifying susceptible patients might be modification of post-transplant immunosuppression with non-diabetogenic agents such as mycophenolate or rapamycin.
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Notes |
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References |
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