 |
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
|
||||
| 2007 JASN IMPACT FACTOR 7.111 | HOME AUTHOR INFO EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP | |||
| CURRENT ISSUE | ARCHIVES | JASN Express | ONLINE SUBMISSION | |
*Department of Internal Medicine and Department of Clinical Epidemiology, University Hospital Maastricht, Maastricht, The Netherlands.
Correspondence to Dr. Elly M. van Duijnhoven, Department of Internal Medicine, University Hospital Maastricht, P.O. Box 5800, 6202 AZ Maastricht, the Netherlands. Phone: +31433877044; Fax: +31433875006; E-mail: evd{at}sint.azm.nl
 |
Abstract |
|---|
 Top Abstract IntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
The development of PTDM can have important sequelae. Miles et al. (15) found a significantly increased frequency of sepsis as a cause of death and a significantly greater risk of developing graft failure in 40 patients with PTDM treated with cyclosporine. There have been suggestions that the diabetic potential of tacrolimus may be higher than that of cyclosporine (12–13,16). Detailed comparisons of glucose metabolism, by use of such techniques as the oral glucose tolerance test or more precise tests, such as the intravenous glucose tolerance test (IVGTT), minimal modeling, euglycemic clamping, and arginine infusion, have mainly been conducted in liver transplant recipients. The only detailed study of glucose metabolism in renal allograft recipients showed more abnormal IVGTTs in patients treated with tacrolimus than in patients who received cyclosporine (17). That study was performed in children and was nonrandomized and cross-sectional. Besides, improvement in glucose metabolism after dose reduction (12–13) indicates that the outcome of a study comparing tacrolimus with cyclosporine may depend on target trough levels.
Herein, we present what is to our knowledge the first prospective, randomized, longitudinal study comparing glucose metabolism by IVGTT in adult renal transplant recipients on tacrolimus versus cyclosporine-based immunosuppression with identical concomitant immunosuppression in the first 3 yr after kidney transplantation. We also describe prospective monitoring for hyperglycemia and PTDM.
|
Material and Methods |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Twenty-three white patients were included in the study. Before surgery, they were randomized to a study group by opening a sealed envelope assigning them to the tacrolimus (n = 11) or cyclosporine (n = 12) groups. At the time of transplantation, both groups were comparable in gender, age, transplantation number, body-mass index (BMI), and primary renal disease (Table 1). During the study, their BMI, renal function (Cockcroft-Gault formula), and the use of drugs that might interfere with glucose metabolism (e.g., antihypertensive drugs, oral contraceptives, phenytoin, pentamidine) were monitored.
|
Rejection was treated with intravenous steroid pulse therapy (0.5 to 1.0 g methylprednisolone on 3 alternate days) and, in the case of steroid resistance, with antithymocyte globulin for 10 d. During antithymocyte globulin administration, daily orally administered prednisolone was continued. At the time of the first dose of antithymocyte globulin, an additional bolus of 25 mg prednisolone was prescribed.
Glucose Metabolism
Glucose metabolism was studied via IVGTT. The tests were performed in the morning after an overnight fast, at week 3, at months 3 and 6, and at years 1, 2, and 3 after renal transplantation. None of the tests was performed during or within 3 wk after rejection treatment. Glucose (0.5 g/kg) was administered intravenously for 2 to 3 min. Blood samples for measurement of whole-blood glucose, C-peptide, and insulin were taken from the opposite arm at t = -15, 0, 5, 10, 15, 20, 30, 40, 50, and 60 min. Insulin sensitivity index (glucose disappearance rate = kG) was calculated by linear regression from the log-transformed glucose values of t = 10 to 30 min. A kG value less than 0.8 mmol/L per minute was considered to be abnormal, between 0.8 and 1.2 mmol/L per minute to be indeterminate, and greater than 1.2 mmol/L per minute to be normal (18,19). C-peptide and insulin secretion—both the increment (the secretion response to a glucose load) and the total secretion (basal + increment)—were calculated as area under the curve by use of a linear trapezoidal technique from the serum value at each time point. With the increment, this was done after subtracting the t = 0 value. Insulin resistance was calculated by use of the insulin/glucose ratio and the homeostasis model assessment (HOMA-R; fasting glucose [mmol/L] x fasting insulin [mU/L]/22.5) (20,21).
During hospitalization, urine was examined daily for glucosuria, and at the outpatient clinic, it was examined during every visit. When glucosuria was detected, whole-blood glucose was examined. When no glucosuria was detected, whole-blood glucose was measured initially at least once every week and later at least every 3 mo. When glucose values were abnormal (more than 6.1 mmol/L in the fasting state or more than 7.8 mmol/L in the nonfasting state) for 2 or more different samples and there was no known explanation, such as additional high-dose steroids or infection, PTDM was diagnosed.
A dipstick method was used for the detection of glucosuria. For the measurement of glucose in whole blood, the CX 7 (Beckman Instruments, Palo Alto, CA) was used, and for C-peptide and insulin, the Autodelfia (Wallac, Turku, Finland) was used. In patients who developed PTDM, fasting glucose levels and fructosamine levels were monitored (Unimate 5 FRUC, ABX, Eindhoven, the Netherlands). Normal reference values from our laboratory were 3.1 to 6.1 mmol/L for fasting glucose, 1.0 to 25.0 mU/L for fasting insulin, 0.12 to 1.20 nmol/L for fasting C-peptide levels, and 0.62 to 1.22 mmol/L for fructosamine.
Statistical Analyses
For statistical analysis, SPSS version 9.0 for Windows (SPSS, Inc., Chicago, IL) was used. For analysis of basic characteristics, the appropriate parametric and nonparametric tests were used. Changes in time and differences between patients who received tacrolimus and cyclosporine were evaluated by ANOVA for repeated measures in 2 separate periods: an early period, from week 3 to month 6 (when patients were still recovering from the operation, when catabolism and immobility gradually improved, and when steroid dose and trough levels gradually decreased) and in a more stable later period, from month 6 to year 3. When Mauchly’s sphericity test was statistically significant, results for univariate tests were given after applying the Greenhouse-Geisser epsilon correction. For correlations between parameters, the Spearman rho rank correlation coefficient was used. Correlations between trough level and parameters of glucose metabolism were evaluated for month 6 to year 3 because only in this period would tacrolimus trough levels correlate adequately with the free levels that are responsible for its actions. P < 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Table 2 shows BMI and renal function up to the third year after transplantation. There were no significant differences in BMI and renal function between patients who received tacrolimus and patients who received cyclosporine at any time. From week 3 to month 6, BMI increased gradually in patients who received cyclosporine, whereas there was an initial decrease of BMI in patients who received tacrolimus, with a gradual increase thereafter. In both groups, creatinine clearance improved gradually during the first 6 to 12 mo. Table 3 shows the antihypertensive drugs (from which at least ß-blockers and diuretics might interfere with glucose metabolism) used at the time of the IVGTT. No one was treated with other drugs known to interfere with glucose metabolism.
|
|
Hyperglycemia or PTDM
In the first 24 h after transplantation, all patients had hyperglycemia while receiving high doses of steroids (median glucose, 17.8 mmol/L; range, 7.5 to 28.8 mmol/L). After this period, 2 patients who received tacrolimus and 1 who received cyclosporine had hyperglycemia for 7 to 14 d during steroid pulse therapy for acute rejection (maximum glucose 9.7, 21.6, and 22.5 mmol/L, respectively). One of the 2 patients who received tacrolimus also had an abnormal glucose level of 12.9 mmol/L during additional steroid administration because of surgical intervention. Two patients who received cyclosporine also had an abnormal glucose level of 10.1 and 9.0 mmol/L, respectively, during additional steroid administration because of surgical intervention.
One patient who received cyclosporine had 2 abnormal fasting glucose levels of maximum 7.8 mmol/L 28 wk after transplantation. Because there was no obvious cause for his hyperglycemia, PTDM was diagnosed. His treatment consisted only of changes in diet. Thereafter, fasting glucoses ranged from 7.1 to 9.5 mmol/L, with normal fructosamine levels of 1.04 and 1.11 mmol/L up to graft failure at month 18.
All other patients had fasting glucose levels less than 6.1 mmol/L and nonfasting glucose levels less than 7.8 mmol/L.
Glucose Metabolism
Tables 4 and 5 show the median levels and range of basal and stimulated parameters of glucose metabolism. Table 6 shows changes in time, as well as differences between patients who received tacrolimus and those who received cyclosporine.
|
|
|
Stimulated Parameters.
In the early period, there was a tendency toward an increase in kG. In both groups, there were several patients with a kG below normal (less than 1.2 mmol/L per minute). At week 3, kG was below normal in 45% of the patients who received tacrolimus and in 17% of the patients who received cyclosporine, and at year 3, in 33% of the patients who received tacrolimus and 36% of the patients who received cyclosporine. Total C-peptide secretion decreased significantly, whereas the increment of C-peptide secretion and insulin secretion (both total and increment) did not change significantly over time. In the later part of the study, there were no significant changes in any of the stimulated parameters.
The increment of C-peptide secretion and the increment of insulin secretion were significantly different for patients who received tacrolimus versus cyclosporine. At week 3, the increment of C-peptide secretion was 57% lower, and the increment of insulin secretion was 48% lower for patients who received tacrolimus than for those who received cyclosporine (26.68 versus 61.44 nmol/min per L and 584.0 versus 1114.6 mU/min per L, respectively). After 3 mo, the differences were no longer significant between the 2 groups (44.65 versus 40.23 nmol/min per L and 821.3 versus 931.9 mU/min per L at month 3, respectively).
Correlations between Trough Level and Parameters of Glucose Metabolism
A weak but statistically significant correlation was found between cyclosporine trough level and both total insulin secretion and increment of insulin secretion (r = 0.312, P = 0.039). Otherwise, tacrolimus and cyclosporine trough levels did not correlate significantly with any of the parameters of glucose metabolism investigated.
|
Discussion |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
Only 1 (4%) patient who received cyclosporine developed PTDM, compared with 5 to 35% in other reports (1–9). In our center, the observed incidence of PTDM, defined as the need for antidiabetic drugs or insulin, in 128 consecutive renal transplant recipients treated with either tacrolimus or cyclosporine was 18.5 and 10.8%, respectively (P = NS, data not shown) over a follow-up period of 18 to 46 mo. Thus, in the group of 23 patients in this study, we would only have expected 2 to 3 patients to develop PTDM. Plausible explanations for the relatively low incidence of PTDM in this study, and in our center in general, are fairly low tacrolimus trough levels and steroid dose, and the fact that most of the patients we studied were white.
In 1 patient, PTDM was diagnosed 28 wk after transplantation. At week 3 and month 3, he already had low insulin sensitivity indexes and extremely low insulin increment secretion levels; his insulin/glucose ratio was below median levels. No other patient had two such low consecutive secretion levels.
Although the incidence of PTDM, with frequent, regular check-ups, was low, approximately 33% of the patients had an insulin sensitivity index below normal (less than 1.2 mmol/L per minute), indicating impaired glucose tolerance. This is a significantly higher incidence than the 17% we found in dialysis patients before treatment with tacrolimus, but a lower incidence than the 56% observed in dialysis patients during treatment with tacrolimus in our previous study (22). A high median tacrolimus trough level of 17.1 ng/ml at the time of the IVGTT in the previous study, compared with median trough levels of 6.6 to 12.2 ng/ml in this study, could possibly account for this difference. In contrast to our previous study, in the study presented here, we could not find a correlation between tacrolimus trough levels and kG, possibly because in this study, tacrolimus trough levels were in a much lower range.
The median kG, and the incidence of kG levels below normal did not change significantly after the first 6 mo. Therefore, there are no indications for chronic cumulative pancreatic toxicity with either calcineurin inhibitor up to 3 yr after renal transplantation. This contradicts the increasing incidence of PTDM reported by Cosio et al. (14) in a retrospective study in renal allograft recipients treated with cyclosporine-based immunosuppression up to 15 yr after transplantation. They did not include patients who developed PTDM during the first month after transplantation. Because this was the period, at least in our center, in which most cases of PTDM on tacrolimus-based immunosuppression developed (22), it is possible that the increased incidence described reflects the natural history of development of diabetes mellitus with increasing age, as would be expected in the general population.
Significant changes over time were found for fasting glucose, HOMA-R, fasting C-peptide, and total C-peptide secretion. All changes occurred in the first 6 mo after transplantation, especially early in the unstable period, between week 3 and month 3. The increase in fasting glucose and HOMA-R indicates an increase in insulin resistance, most likely related to the increase in BMI, which, after renal transplantation, is predominantly due to augmentation of body fat mass (23). It is unlikely that this increase in insulin resistance was caused by the immunosuppression because both steroid dose and calcineurin inhibitor trough levels decreased in this period. In patients who received tacrolimus, BMI decreased initially, probably because at week 3, many patients who received tacrolimus had access fluid as a result of late onset of graft function.
Although there was a tendency for basal insulin levels to increase, basal C-peptide and total C-peptide secretion levels decreased significantly in the first 6 mo after transplantation. Because C-peptide is almost completely cleared by the kidney (24), this decrease was due to the improvement in graft function over this period: from week 3 to month 6, median creatinine clearance increased considerably from 36 to 52 ml/min (Wilcoxon signed-rank test, P < 0.0001). The subnormal creatinine clearance also explains the fact that fasting C-peptide levels were above levels found in healthy subjects. It seems unlikely that the acute response of the pancreas, responsible for the increment of C-peptide secretion, is influenced by renal function.
At the different IVGTTs, there was quite a large variability in the median parameters of glucose metabolism, especially of insulin-related parameters. The most noticeable variation occurred for insulin/glucose ratio and insulin secretion increment from year 1 to year 2. At that time, there were no significant changes in BMI, renal function, calcineurin inhibitor level, steroid dose, or antihypertensive drugs. We verified that there was no technical failure in the measurement of insulin; the low insulin levels had not been determined in the same run, and quality control had been adequate for all insulin levels at year 2. We compared the insulin glucose levels and insulin secretion increment levels at year 1 with the levels at year 2 (paired t test). Both were not significantly different (P = 0.23 and P = 0.31, respectively). Therefore, normal individual changes must have been responsible for the variability in the results.
The tendency toward improvement in the insulin sensitivity index in the first 6 mo after transplantation suggests a general improvement in glucose metabolism. Explanations for the lower kG at week 3 include higher calcineurin inhibitor levels, a higher dosage of steroids, catabolic state, immobility, and operative stress early after transplantation. Moreover, the free levels of tacrolimus are higher because of hypalbuminemia and anemia. The initially lower kG correlates with the period in which PTDM is usually diagnosed, observed both during our clinical practice and in our earlier study (22): all patients who developed PTDM while on tacrolimus did so in the first 6 mo after renal transplantation.
The kG is determined by the balance between pancreatic secretion capacity (the increment of C-peptide and insulin secretion) and insulin resistance (insulin/glucose ratio and HOMA-R). Despite a rise in insulin resistance, kG improved in the first 6 mo after transplantation as a result of a rise in pancreatic secretion capacity. Therefore, we conclude that abnormalities in glucose metabolic control caused by calcineurin inhibitors are due to a decreased pancreatic secretion capacity and not to increased resistance. In the case of tacrolimus, this may be caused by an inhibition of calcineurin in ß cells as a result of an mRNA transcriptional defect (25). Thus, the results of this study, as well as those of our previous study (22), refute suggestions of an increase in insulin resistance due to calcineurin inhibitors (3,4,9) as a cause of PTDM.
The only significant difference in glucose metabolism found between the tacrolimus and cyclosporine groups was a lower increment of C-peptide and insulin secretion at week 3 for patients who received tacrolimus compared with those who received cyclosporine, indicating a lower pancreatic secretion capacity. Although not statistically significant, kG was also lower at week 3 for the patients who received tacrolimus. After 3 mo, the increment of C-peptide and insulin secretion in patients who received tacrolimus had risen to the same levels as in patients who received cyclosporine. Elmer et al. (26) showed that differences detected between pancreatic allograft recipients treated with tacrolimus and cyclosporine were influenced by steroid dose. At 15 mg prednisolone per day, they found an increased risk of diabetogenicity for patients who received tacrolimus, whereas they did not detect any significant differences at doses of 20 to 30 mg/d. Perhaps the influence of high steroid doses on glucose metabolism was so large that differences due to calcineurin inhibitors could not be detected. In our study, we only detected differences at week 3 and not thereafter. At low steroid doses, the (free) levels of the calcineurin inhibitors at the time of comparison may be the most important factor determining the outcome. At the relatively low target trough levels for both calcineurin inhibitors in this study, this did not result in important long-term differences in glucose metabolism.
In summary, although only 1 patient treated with cyclosporine developed PTDM during the 3-yr prospective follow-up of glucose metabolism, impaired glucose metabolism (kG <1.2) was seen in approximately 1 of 3 patients treated with either tacrolimus or cyclosporine. In the early period after transplantation, kG improved because of a rise in secretion capacity, despite a concomitant increase in insulin resistance. After 6 mo, there were no changes in glucose metabolism, as revealed by IVGTT. Thus, there were no indications of chronic, cumulative, pancreatic islet cell toxicity as a result of long-term use of either tacrolimus or cyclosporine. At week 3, pancreatic secretion capacity, as measured by the increment of C-peptide and insulin secretion, was significantly lower in patients who received tacrolimus than in those who received cyclosporine, probably because of high free tacrolimus levels. After week 3, there were no significant differences between patients who received tacrolimus and patients who received cyclosporine in any of the parameters of glucose metabolism.
|
Footnotes |
|---|
|
References |
|---|
|
TopAbstractIntroductionMaterial and MethodsResultsDiscussionReferences |
|---|
This article has been cited by other articles:
 |
|
 |
|
  D. R. J. Kuypers, K. Claes, B. Bammens, P. Evenepoel, and Y. Vanrenterghem Early clinical assessment of glucose metabolism in renal allograft recipients: diagnosis and prediction of post-transplant diabetes mellitus (PTDM) Nephrol. Dial. Transplant., June 1, 2008; 23(6): 2033 - 2042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. C. J. Gelens, M. H. L. Christiaans, and J. P. van Hooff Glucose metabolism before and after conversion from cyclosporine microemulsion to tacrolimus in stable renal recipients Nephrol. Dial. Transplant., February 1, 2008; 23(2): 701 - 706. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. D. Bloom and P. P. Reese Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation J. Am. Soc. Nephrol., December 1, 2007; 18(12): 3031 - 3041. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Y. Hur, M. S. Kim, Y. S. Kim, E. S. Kang, J. H. Nam, S. H. Kim, C. M. Nam, C. W. Ahn, B. S. Cha, S. I. Kim, et al. Risk Factors Associated With the Onset and Progression of Posttransplantation Diabetes in Renal Allograft Recipients Diabetes Care, March 1, 2007; 30(3): 609 - 615. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. F. Crutchlow and R. D. Bloom Transplant-Associated Hyperglycemia: A New Look at an Old Problem Clin. J. Am. Soc. Nephrol., March 1, 2007; 2(2): 343 - 355. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. C Webster, R. C Woodroffe, R. S Taylor, J. R Chapman, and J. C Craig Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: meta-analysis and meta-regression of randomised trial data BMJ, October 8, 2005; 331(7520): 810. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Teutonico, P. F. Schena, and S. Di Paolo Glucose Metabolism in Renal Transplant Recipients: Effect of Calcineurin Inhibitor Withdrawal and Conversion to Sirolimus J. Am. Soc. Nephrol., October 1, 2005; 16(10): 3128 - 3135. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Midtvedt, J. Hjelmesaeth, A. Hartmann, K. Lund, D. Paulsen, T. Egeland, and T. Jenssen Insulin Resistance after Renal Transplantation: The Effect of Steroid Dose Reduction and Withdrawal J. Am. Soc. Nephrol., December 1, 2004; 15(12): 3233 - 3239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. A. Artz, J. M.M. Boots, G. Ligtenberg, J. I. Roodnat, M. H.L. Christiaans, P. F. Vos, H. J. Blom, F. C.G.J. Sweep, P. N.M. Demacker, and L. B. Hilbrands Improved Cardiovascular Risk Profile and Renal Function in Renal Transplant Patients after Randomized Conversion from Cyclosporine to Tacrolimus J. Am. Soc. Nephrol., July 1, 2003; 14(7): 1880 - 1888. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. M. Cho, K. S. Park, H. S. Jung, H. J. Jeon, C. Ahn, J. Ha, S. J. Kim, B. D. Rhee, S. Y. Kim, and H. K. Lee High Incidence of Tacrolimus-Associated Posttransplantation Diabetes in the Korean Renal Allograft Recipients According to American Diabetes Association Criteria Diabetes Care, April 1, 2003; 26(4): 1123 - 1128. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. R. J. Kuypers and Y. C. Vanrenterghem Tailoring immunosuppressive therapy Nephrol. Dial. Transplant., December 1, 2002; 17(12): 2051 - 2054. [Full Text] [PDF]
|
|
|
|
|
|
J. M. M. Boots, E. M. van Duijnhoven, M. H. L. Christiaans, B. H. R. Wolffenbuttel, and J. P. van Hooff Glucose Metabolism in Renal Transplant Recipients on Tacrolimus: The Effect of Steroid Withdrawal and Tacrolimus Trough Level Reduction J. Am. Soc. Nephrol., January 1, 2002; 13(1): 221 - 227. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
HOME
CURRENT ISSUE
ARCHIVES
JASN Express
ONLINE SUBMISSION
AUTHOR INFO
EDITORIAL BOARD SUBSCRIBE FEEDBACK ALERTS HELP |
