American Journal of Kidney Diseases, Vol 34, No 1 (July), 1999: pp 1-13
© 1999

 

Risk for Posttransplant Diabetes Mellitus With Current Immunosuppressive Medications

Matthew R. Weir, MD1 and Jeffrey C. Fink, MD1

1 From the Department of Medicine, Division of Nephrology, University of Maryland School of Medicine, Baltimore, MD.

ABSTRACT

With improvements in the practice of transplantation and the introduction of new immunosuppressive medications, there has been a substantial increase in 1-year allograft survival rates. Consequently, the pool of potential candidates for organ transplants continues to grow and a greater preponderance of older patients with more comorbidities are undergoing transplantation. As a result, there is interest in such medical complications as posttransplantation diabetes mellitus (PTDM) that develop after the transplantation of a successful allograft. PTDM is an undesirable consequence of transplantation because of its associated morbidity and impairment of both patient and graft survival. Although some controversy exists, it is likely that glucose intolerance after transplantation results in both macrovascular and microvascular disease, and there is an increasing risk for infectious and cardiovascular diseases, to which transplant recipients are already at increased susceptibility. Both experimental and clinical observations have shown that immunosuppressive agents currently used in transplantation account for a large degree of the increased risk for PTDM. Consequently, improved understanding of the effects of currently used immunosuppressive medicines on glycemic tolerance is of interest in clinical transplantation.

IN AN ERA in which successful renal transplantation can be offered to a growing number of patients with end-stage renal disease, there is increasing concern about the complications that develop after the transplantation of a functioning allograft. One of the more significant adverse complications in this setting is posttransplant diabetes mellitus (PTDM), because this is often unanticipated by the patient and has the potential to lead to poor outcomes. As the transplant community has used more effective strategies with immunosuppressive agents to decrease the incidence of acute rejection and improve graft survival, due consideration must be given to the occurrence of PTDM and its impact on overall patient outcome. This review discusses risk factors for the development of PTDM and potential adverse outcomes from this posttransplant complication. In addition, the discussion focuses on the diabetogenicity of the primary immunosuppressants currently used in practice and how the risk for diabetes can be mitigated.

DEFINITION OF PTDM

The difficulty interpreting the literature on the frequency of PTDM stems from the varied definitions of this disease. Also, glucose intolerance and/or subtle diabetes mellitus may be asymptomatic for years before becoming clinically manifest; therefore, the exact frequency of PTDM and associated clinical sequelae is not well known. Recently, the National Diabetes Data Group and the World Health Organization (WHO) defined impaired glycemic control as a blood glucose level greater than 140 mg/dL at a 2-hour time point during an oral glucose tolerance test, and clinical diabetes as a serum glucose level greater than 200 mg/dL at this same time point.1

Most definitions for PTDM in the literature are derived from random glucose testing or fasting glucose levels greater than 140 mg/dL.2 -9 Unfortunately, none of these clinical trials have routinely included oral glucose tolerance tests to determine the exact incidence of glycemic abnormalities in transplant recipients. As an example of the heterogeneity in the literature, Jindal2 defined PTDM as a fasting glucose level greater than 200 mg/dL for 2 weeks or greater than 400 mg/dL at any single time point. Boudreaux et al3 diagnosed PTDM based on two fasting blood glucose levels greater than 140 mg/dL, whereas Rao et al4 defined glucose intolerance as three fasting blood glucose levels exceeding 140 mg/dL (Table 1).



Table 1. Relationship Between Definition and Incidence of Posttransplant Diabetes Mellitus

Reference

Definition of PTDM

Immunosuppression

Pred/AZA (%)

Pred/CSA (%)

Pred/AZA/CSA (%)

Boudreaux et al3

2 Fasting glucoses >140 mg/dL and abnormal OGTT

6.4

6.9

19.1

Mejia et al5

2 Serum glucoses >200 mg/dL

3.3

11.2

—

Roth et al9

3 Fasting glucoses >140 mg/dL

9.1

18.6

—

Yoshimura et al44

Requirement for insulin

12.8

17.1

—

Sumrani et al8

3 Fasting glucoses >150 mg/dL or abnormal OGTT

11.6

—

 

Hricik et al35

Requirements for insulin

9.6

—

12.9

Abbreviations: Pred, prednisone; AZA, azathioprine; CSA, cyclosporine; OGTT, oral glucose tolerance test.

 

RISK FACTORS FOR PTDM

Several risk factors have been identified for the development of PTDM (Table 2). The most important of these is increasing age; transplant recipients who develop PTDM are consistently older than patients without this complication.3 ,4 ,7 ,10 -12 A family history of diabetes and abnormal glucose tolerance parameters before transplantation may also increase the risk for developing PTDM.8 ,10 ,13 Some studies have also shown that black and Hispanic transplant recipients are at a particularly high risk for developing PTDM.7 ,8 ,<14 -17 Other factors inconclusively linked with the development of PTDM include increasing body weight,3 ,7 ,9 transplantation with a cadaveric kidney,3 ,7 ,8 and certain HLA types, including: HLA-A28,18 HLA-A30,8 HLA-B8,19 HLA-B18,19 HLA-Bw15,19 HLA-Bw42,8 and HLA-Dw16.19



Table 2. Risk Factors for Posttransplant Diabetes Mellitus

Conclusive risk factors

 Increasing age

 Family history of diabetes

 Abnormal glucose tolerance pretransplantation

 Black and Hispanic descent

Inconclusive risk factors

 Increasing body weight

 Cadaveric transplant

 HLA-types A28, A30, BM8, B18, Bw15, Bw42, Dw16


IMPACT OF PTDM ON OUTCOME

It generally has been accepted that both juvenile and mature-onset diabetes mellitus in patients who did not undergo transplantation, when poorly controlled, are associated with a greater risk for morbidity and mortality.20 -24 The increased incidence of vascular and infectious complications seen with diabetes mellitus almost certainly complicates the outcome of patients with PTDM.

Because both hyperinsulinemia and hyperglycemia are known to promote atherosclerosis,22 -24 PTDM probably contributes to the high prevalence of death from cardiovascular disease seen in this population.25 Furthermore, the preponderance of infections associated with diabetes mellitus is likely to increase the risk for sepsis in the transplant population. Sumrani et al8 described the outcome of 39 patients with PTDM from a cohort of 337 cyclosporine (CSA)-treated renal transplant recipients. They reported infections were a major complication in the PTDM group; 53% had infectious complications compared with 16% of the controls. The investigators were not able to show a significant difference in mortality between those patients with PTDM compared with controls; however, all five deaths in the PTDM group were caused by sepsis, compared with one death from sepsis in the non-PTDM patients.8 Miles et al26 also failed to show a significant difference in mortality rate between 40 patients with PTDM (27%) and 40 renal transplant controls (20%) after 12 years of observation. However, the frequency of sepsis as a cause of death was greater in the PTDM group, accounting for 46% of the deaths compared with 12% in the controls.26 The lack of cardiovascular disease as a cause of increased mortality in patients with PTDM may be caused by limited follow-up in the observational studies.

PTDM is also likely to be responsible for an increased incidence of graft failure8 ,9 ,26 ; however, to what extent this is caused by the development of diabetic nephropathy is not clear. Sumrani et al8 reported no difference in the rate of decline in renal function comparing patients with PTDM to control patients; but the actuarial 5-year graft survival of patients with PTDM was 70% compared with 90% in controls. The causes of 12 graft losses in the PTDM group included 6 grafts lost to chronic rejection, three deaths with a functioning graft, 2 grafts lost to noncompliance, and 1 graft lost to sepsis.8 In a multivariate analysis of their study group, Miles et al26 found that the patients with PTDM were at a greater risk for developing graft failure (relative risk = 3.72; P = 0.04) than the control patients, and no other significant predictors were identified in the regression analysis. Ten of the 17 patients who lost their grafts in that study underwent renal biopsies at 1 year, and 2 patients had findings consistent with diabetic nephropathy.26

There are several potential ways in which PTDM can have an impact on the kidney. Certainly, diabetic nephropathy can ensue, as shown in the study by Miles et al26 ; however, in most cases, diabetic nephropathy may take several years to develop. The presence of poorly controlled hypertension, common in this population, is likely to accelerate glomerular injury.27 Hyperglycemia itself may upregulate the synthesis of such soluble mediators of fibrosis in the kidney as transforming growth factor-ß, which may be important in promoting mesangial matrix expansion and mesangial cell hyperplasia.28 These growth factors are likely to have a role in the development of chronic allograft nephropathy, which was the predominant cause of graft loss in the observational studies of graft outcome with PTDM. In the studies by Sumrani et al8 and Miles et al,26 there was a high incidence of graft loss from chronic allograft nephropathy in the patients with PTDM compared with their counterparts without diabetes.

EFFECTS OF IMMUNOSUPPRESSIVE AGENTS ON GLYCEMIC TOLERANCE

Corticosteroids
Corticosteroids have always been the primary agent used in immunosuppressive strategies for transplantation and, before the CSA era, PTDM was referred to as steroid diabetes. The development of PTDM in renal transplant recipients receiving steroids has been reported to be as high as 46%29; however, a dose relationship is likely, shown by a lower rate of PTDM on relatively low steroid maintenance doses.30 -32 Attempts to reduce steroid doses or even withdraw steroids in the past were associated with a substantial risk for late rejection,33 but the introduction of CSA has allowed more aggressive attempts at steroid withdrawal and evaluation of the role of steroids in the development of PTDM in the clinical setting.

Hricik et al34 showed the hyperglycemia of patients with PTDM after transplantation can be significantly improved with tapered daily steroid doses. In a comparison of the incidence of PTDM found in renal allograft recipients on an immunosuppressive regimen including CSA, prednisone, and azathioprine and a historical cohort of renal transplant recipients receiving prednisone and azathioprine, Hricik et al34 reported the onset of PTDM in 9 of 70 patients (12.9%) who previously did not have diabetes. This incidence compared with 8 of 83 renal transplant recipients (9.6%; P = not significant) receiving only azathioprine and prednisone. Seven of the renal transplant recipients (and an additional recipient of a combined kidney-pancreas transplant) on triple-drug immunosuppression therapy were successfully withdrawn from prednisone. Seven of the eight patients withdrawn from prednisone were able to discontinue their hyperglycemic therapy of either insulin or oral hypoglycemic agents within 4 months of steroid cessation. The mean glycohemoglobin level declined significantly from 10.6% ± 3.6% before steroid withdrawal to 6.0% ± 3.6% a month after steroid cessation. Of note, two of the patients who underwent steroid withdrawal developed acute rejection and had to resume steroid therapy. One of these patients required reinstitution of insulin, whereas the other patient had never discontinued insulin after withdrawal from prednisone.35

In a randomized study to evaluate steroid withdrawal in 84 renal transplant recipients, there was a reduction in the frequency of PTDM by 10% in the steroid-withdrawal patients and a 0.4-mmol/L decrease in the glycosylated hemoglobin level compared with the patients maintained on steroids.36 In this controlled study, 26% of those patients who were withdrawn from steroids subsequently resumed steroid use because of the onset of acute rejection. These studies highlight the role of steroids in the development of PTDM; however, they also show steroid withdrawal is wrought with a high risk for acute rejection, which might in turn increase steroid requirements and the subsequent incidence of PTDM.

PTDM related to steroid use, much like non–insulin-dependent diabetes mellitis, has been assumed to be a function of insulin resistance with a concomitant relative deficiency in insulin production. The case for a high degree of insulin resistance has been well established. In six volunteers without diabetes who received intravenous cortisol, Rizza et al37 showed a substantial increase in baseline glucose and insulin levels compared with the saline-infusion period. During insulin infusion, the intravenous glucose requirements to maintain euglycemia were less during the period of cortisol administration compared with the control period except at the greatest insulin dose. In addition, cortisol had the effect of increasing the amount of insulin needed to decrease glucose utilization and suppress endogenous glucose production.37 Other investigators suggested the mechanism of insulin resistance included decreased insulin receptor number and affinity, impaired glucose uptake by muscle, or activation of glucose-free fatty acid cycle.38 ,39

There is also some evidence to suggest steroid use has the additional effect of leading to insulin deficiency. Kalhan and Adam40 showed an inhibitory effect of prednisolone on insulin secretion in humans. In 1974, Hill et al41 detected glycosuria in a large number of renal transplant recipients treated with azathioprine and steroids at their center and reported the results of subsequent glucose tolerance testing. There were abnormal glucose tolerance test results in 12 of 17 patients with glycosuria. Whereas fasting insulin levels were normal in the 12 patients, the insulin response to oral glucose was diminished in all patients, suggesting a suppression of insulin production by steroids.41 These results were in contrast to another study of 10 steroid-treated renal transplant recipients, 6 of whom also received CSA, in which suppression of insulin secretion was not shown with oral glucose tolerance testing.42

Cyclosporine
After the introduction of CSA, the reported incidence of PTDM decreased significantly to between 3% and 20%.2 -4 ,8 ,35 ,43 ,44 This reduction in the incidence of PTDM was largely related to the trend toward decreasing the amounts of corticosteroids needed for prophylaxis and treatment of acute allograft rejection. However, CSA also has diabetogenic effects,46 and the earlier estimates of the incidence rates of PTDM were between 11% to 19%.3 ,5 ,9 ,44 As dosages of CSA and steroids have decreased more recently, PTDM has been reported in 3% to 14% of transplant recipients.4 ,8 ,35 ,43 ,44 However, within-center comparisons of patients receiving CSA-based regimens to those transplant recipients receiving azathioprine and prednisone have shown no significant differences in the incidence of PTDM between the two types of regimens.

Boudreaux et al3 compared the incidence of PTDM in patients receiving CSA, prednisone, and azathioprine who underwent transplantation between 1984 and 1985 with an earlier cohort of patients (1980 to 1983) randomized to receive a regimen of either CSA and prednisone or antilymphocyte globulin, azathioprine, and prednisone. There was no difference in the incidence of PTDM between the treatment arms of the randomized study (6.9% v 6.4%); however, the later cohort that received CSA had a significantly greater rate of PTDM (19.1%; P < 0.05) despite a lower dose of both CSA and prednisone than the earlier group. The investigators attributed the greater rate of PTDM in the later cohort to older and heavier transplant recipients in the group.

Yoshimura et al44 reported a greater incidence of PTDM requiring insulin in their transplant recipients treated with CSA (18 of 105 patients; 17.1%) compared with historical controls receiving azathioprine and prednisone (23 of 180 patients; 12.8%; P < 0.05), although the patients treated with CSA had a lower average steroid dose. Insulin was eliminated within 3 months in six of eight patients who discontinued CSA therapy. Furthermore, the ratio of insulin level to blood glucose level, referred to as the insulinogenic index, increased in all patients converted to lower doses of CSA in contrast to no index change in patients who had reductions in prednisone dosing.44

The use of provocative testing of glucose metabolism and insulin secretion has shown a greater incidence of glucose intolerance and diabetes after transplantation than reported with clinical observation alone. In prospective, randomized, multicenter trials, the incidence of PTDM with CSA-based immunosuppression has been reported to be as low as 2% to 5%.>45 ,46 However, the criteria for diagnosis in these studies only required that patients be treated with insulin for 30 days or more, which classified untreated hyperglycemia or treatment with oral hypoglycemic agents as nondiabetic and understated the incidence of this complication. In the previously described study conducted by Hricik et al35 of patients who underwent steroid withdrawal, follow-up glucose tolerance testing in four patients successfully withdrawn from insulin after cessation of prednisone continued to detect hyperglycemia. Ekstrand et al47 showed in 10 renal transplant recipients, 7 treated with CSA and all with normal oral glucose tolerance, that there was a substantial increase in insulin secretion to maintain normoglycemia compared with healthy controls. Teuscher et al,48 using the more sensitive arginine-stimulated insulin secretion test, was able to detect significant beta cell dysfunction in normoglycemic simultaneous kidney-pancreas transplant recipients treated with CSA.

The diabetogenic effect of CSA has been difficult to show in some studies in which patients did not receive steroids, which raised the hypothesis that there may be an interaction between prednisone and CSA that could result in more adverse effects than with either agent alone. CSA has the potential to inhibit the metabolism of steroids by the P-450 system, thereby increasing the level of steroids and the frequency of such toxicities as PTDM.49 Cantarovich et al50 reported on 28 renal transplant recipients receiving CSA without steroids in the maintenance immunosuppression regimen, and no patients had detectable abnormalities in glucose metabolism or insulin secretion as measured with oral glucose tolerance testing. In one prospective study of renal transplant recipients randomized to receive one of four immunosuppressive regimens, PTDM was not observed in 32 patients receiving CSA without steroids, although the patients only underwent oral glucose tolerance testing to screen for PTDM.12 Robertson et al51 conducted a randomized, double-blind study of CSA use in patients with multiple sclerosis and used intravenous glucose tolerance testing and insulin secretion studies to screen for diabetes. Although CSA was administered in doses equivalent to those seen in renal transplant recipients, there was no observed impairment of glucose tolerance for up to 2 years of observation. The study highlighted the likely interaction between the baseline susceptibility for diabetes of many individuals with renal disease and kidney transplants compared with patients with other chronic diseases.

Along with the potential interaction of CSA with steroids and increased insulin resistance, the mechanism by which CSA leads to PTDM probably involves diminished insulin production, inhibited secretion of insulin, and a reduction in beta cell volume.52 -62 Wahlstrom et al52 showed that when CSA was administered to dogs in therapeutic doses, there was a reduction in insulin secretion on stimulation with glucagon. The effect on insulin secretion was greater at 20 than 15 mg/kg/d of CSA. In addition, there was increased insulin resistance shown with euglycemic clamp studies. All effects related to CSA were reversible after cessation of the drug, but the investigators suggested the observed abnormalities might be slower to return to normal after prolonged treatment. Hahn et al53 studied the toxic effect of CSA on pancreatic beta cells in Wistar rats treated for 2 weeks with CSA at either 50 or 15 mg/kg/d. There was significant glucose intolerance in the rats exposed to 50 mg/kg/d of CSA and a marked reduction in pancreatic extract insulin content. Diminished beta cell density was observed at both doses of CSA. When challenged with glucose stimulation, the islet extracts had a reduction in insulin secretion, most significantly at the 50-mg/kg/d dosage of CSA.53 In a follow-up study, the investigators showed that at the 50-mg/kg/d dosage, there was a 50% reduction in DNA synthesis in the islets of the CSA-treated animals compared with that measured in the control animals. Three weeks after withdrawal of CSA, DNA synthesis was enhanced in the islets, with resolution of glucose intolerance and beta cell density by 8 weeks.54 Eun et al55 used a similar model of Wistar rats treated for 7 days with CSA at 40 mg/kg/d and showed severe cytoplasmic vacuolization in the islet cells of treated animals on light microscopy. Electron microscopy showed degranulation and dilatation of the endoplasmic reticulum in beta cells of the treated rats. Furthermore, islet cells isolated from the CSA-treated animals had a 50% reduction in messenger RNA (mRNA) expression. Using in vitro preparations of human islet cells exposed to CSA at a concentration of 10 µg/mL, the investigators also reported diminished mRNA synthesis. Andersson et al56 showed that mouse pancreatic islets cultured in the presence of CSA not only had impaired DNA synthesis, but also diminished proinsulin biosynthesis when exposed to high glucose concentrations.

Although many studies conclude that the cause of impaired insulin secretion related to CSA is decreased DNA expression and insulin synthesis, other investigators have reported findings that suggest the defect is in the secretion of insulin. Neilsen et al60 cultured human islet cells exposed to CSA concentrations of 100 ng/mL. The insulin content of the human islets exposed to CSA were on average 59% greater than in the control preparations; however, insulin secretion in response to glucose exposure was diminished by 36%. In an in vitro pancreas infusion model, Gillison et al61 showed that CSA leads to a suppression of both first- and second-phase insulin release on glucose challenge and suggested there was both a marked depletion in insulin synthesis and an independent inhibition of insulin secretion. In a separate study, Gillison et al62 showed somatostatin-mediated inhibition of insulin secretion was intact in CSA-exposed pancreas preparations, but arginine stimulation of insulin secretion was reduced whereas glucagon release was intact. Calmodulin may be an important mediator of insulin secretion given its affinity for CSA. That a calmodulin inhibitor, trifluoperazine, restored the insulin secretory capacity of pancreatic islets suppressed by exposure to CSA supported this hypothesis.58

Tacrolimus
Use of the newer calcineurin inhibitor, tacrolimus (FK506), was expected to minimize PTDM as a complication in transplant recipients because of its immunosuppressive potency and further potential to decrease the need for steroids. The earliest experience with tacrolimus was in liver transplantation, in which PTDM was still noted with some frequency. Todo et al63 first described the association of PTDM with tacrolimus in a cohort of 121 liver transplant recipients, 10 of whom developed insulin-requiring PTDM after transplantation. This observation was confirmed by several other reports of liver transplant recipients, many of whom were maintained on lower steroid doses than previously used with CSA-based regimens. Krentz et al64 performed a comparative study of the diabetogenic effects of CSA versus tacrolimus in liver transplant recipients after the withdrawal of steroids. Results of oral glucose tolerance testing were compared in 10 transplant recipients receiving CSA-based immunosuppression and 10 patients on a tacrolimus-based regimen, with all study subjects withdrawn from steroids at least 6 weeks before the study. At 120 minutes after the oral ingestion of 75 g of glucose, the average whole-blood glucose concentration of both tacrolimus and CSA patients was greater than that of healthy controls. Of note, the average glucose concentration in the tacrolimus-treated subjects at 120 minutes was also significantly greater than that for the CSA-treated patients. Four of the 10 CSA-treated patients met WHO criteria for impaired glucose tolerance, whereas 4 of the tacrolimus-treated patients had impaired glucose tolerance, and an additional 3 patients met the criteria for overt diabetes. Serial measurement of plasma immunoreactive insulin levels in the study patients during the oral glucose tolerance test showed elevated insulin levels for both study groups compared with healthy controls. Therefore, after liver transplantation, both CSA and tacrolimus independent of steroids were associated with impaired glucose tolerance and hyperinsulinemia rather than diminished secretion. The hyperglycemic effects of tacrolimus appeared to be more potent than those of CSA.

Clinical data in renal transplant recipients receiving tacrolimus has not been as extensive as for CSA, and the role of hypoinsulinemia versus insulin resistance as a primary cause of PTDM remains unclear. Renal transplant recipients receiving tacrolimus have an incidence of PTDM ranging from 15% to 29%.63 -66 Scantlebury et al65 found that 4 of 20 patients treated with tacrolimus as the primary immunosuppressive agent after renal transplantation initially required insulin. In a larger study of 395 patients treated with tacrolimus and prednisone with or without azathioprine, Shapiro et al67 reported that 18% of the patients initially required insulin.

It is possible that PTDM associated with tacrolimus may be dose related and decrease over time. In the study by Shapiro et al,67 40% of the patients receiving tacrolimus initially diagnosed with PTDM were weaned off insulin with lower doses of tacrolimus and steroids. In liver transplant recipients, the average serum glucose level of patients correlated with serum trough tacrolimus levels.68 In most reports of tacrolimus-induced PTDM in renal transplant recipients, the prevalence of patients requiring insulin diminished over time, with a reversibility of PTDM in 37% to 83% of patients.69 ,70

There are a limited number of animal studies investigating the impact of tacrolimus versus CSA on pancreatic islet cells; however, the effect appeared to be similar.71 -74 Hirano et al71 administered tacrolimus at either 1, 5, or 10 mg/kg/d to groups of Sprague-Dawley rats for 14 days. The animals then underwent glucose tolerance testing that showed mild hyperglycemia but no decrement in insulin secretion at the lower dosages of tacrolimus. At the 10-mg/kg/d dosage of tacrolimus, there was marked hyperglycemia and diminished insulin secretion; however, glucose metabolism and insulin secretion returned to normal after cessation of the drug. The investigators showed similar results in CSA-fed animals.71 Strasser et al74 administered tacrolimus, 1 mg/kg/d, orally to beagles for either 2 or 4 weeks and showed diminished glucose disposal with an intravenous glucose tolerance test in both study groups. The investigators also showed no change in insulin secretion in the animals treated for 2 weeks; however, in those animals with more prolonged administration, there was decreased insulin secretion that was only partially reversible with cessation of the drug.74

The effect of dosage of tacrolimus on insulin secretion was further evaluated in mice that received human pancreatic islets transplants.75 At a dosage of 0.3 mg/kg/d administered to the peritoneum for a week, there was no effect on glucose tolerance in the mice, whereas at dosages of 1 and 3 mg/kg/d, there was a decreased rate of glucose disappearance and diminished C-peptide response. These alterations in glucose tolerance and insulin secretion observed with tacrolimus use have been associated with morphological changes to the islet cells, including significant vacuolization and degranulation that frequently resolved with discontinuation of the drug.71 There is evidence in animals that the defect in insulin secretion induced by tacrolimus is related to inhibition of synthesis. Tamura et al76 showed that the defect in insulin synthesis is caused by an mRNA transcriptional defect dependent on duration of exposure to tacrolimus. In Sprague-Dawley rats administered tacrolimus, 10 mg/kg/d for up to 14 days, the investigators showed a significant decrease in immunohistochemical staining for anti-insulin antibody, whereas there was no change in staining for glucagon. Similarly, in situ hybridization of insulin mRNA progressively decreased from 1 to 14 days after initiation of tacrolimus therapy; however, mRNA transcription returned to normal after discontinuation of the drug. Because of a high presence of FK506–binding protein-12 and, to a lesser degree, calcineurin in the beta cells of the rat islets, the investigators hypothesized that the defect in mRNA transcription induced by tacrolimus was mediated by binding to FK506–binding protein-12 and subsequent inhibition of calcineurin in beta cells.

The conclusions of most experimental studies of tacrolimus-induced PTDM are to some extent discordant with the observations reported in transplant recipients. Whereas clinical studies have suggested that hyperinsulinemia and insulin resistance are the basis for PTDM in transplant recipients treated with tacrolimus, studies of animals document significant pancreatic islet cell toxicity and diminished insulin secretion. Observations that drug withdrawal mitigates the effects of tacrolimus on islet cells are consistent with the decreased incidence over time of PTDM in patients receiving tacrolimus when levels are reduced. However, delineating whether insulin resistance, diminished insulin secretion, or both is the primary cause of PTDM in the clinical setting will have significant therapeutic implications.

COMPARATIVE CLINICAL TRIALS OF IMMUNOSUPPRESSIVE AGENTS AND THE RISK FOR PTDM

Randomized trials designed to evaluate the efficacy of CSA versus tacrolimus as primary immunosuppressive agents in renal transplant recipients have provided an opportunity to make a direct comparison of the diabetogenicity of the two agents (Table 3 ). The European Tacrolimus Multicenter Renal Study Group performed an open-label, randomized trial involving 15 centers, with 145 patients randomized to receive CSA and 303 patients to receive tacrolimus.45 The definition of PTDM for this clinical trial was the use of insulin for more than 30 days in patients not receiving insulin before transplantation. Corticosteroid therapy involved approximately 625 mg of methylprednisone the first 2 days posttransplantation, followed by prednisone, 20 mg daily for days 2 through 14, with a progressive taper to 5 mg daily by 6 weeks. The investigators reported the initial incidence of insulin-dependent diabetes mellitus was 8.3% in tacrolimus-treated patients compared with 2.2% in the CSA group. The percentage of tacrolimus patients receiving insulin at 12 months decreased to 5.5%, and the corresponding percentage of patients receiving CSA remained at 2.2%. Multivariate analysis indicated that increasing tacrolimus whole-blood concentrations were associated with a greater risk for developing PTDM. In this clinical trial, mean blood levels (12-hour trough) of tacrolimus and CSA were 13.9 and 254.3 ng/mL, respectively, during the first 3 months posttransplantation, whereas during the last 3 months of the 1-year clinical trial, they averaged 9.4 and 93.2 ng/mL, respectively. It is unlikely, based on the low doses of corticosteroids used in this study, that they contributed substantially to the development of PTDM.


Table 3. Comparison of Risk for Posttransplant Diabetes Mellitus With Cyclosporine or Tacrolimus

Source

Definition of PTDM

Incidence of PTDM

Comments

 

CSA (%)

FK506 (%)

P

 

 

Pirsch et al15

Insulin use for >=30 d in pts with no history of DM

4

19.9

<0.001

Open-label, randomized multicenter (n = 19) study

 

CSA (n = 207), FK506 (n = 205)

 

IDDM reversed in 16% of FK506 (5/30) and CSA (1/6) pts

 

PTDM significant predictors: race, steroid dose, and FK506 levels

 

Mayer et al45

Insulin use for >30 d in pts not receiving insulin at baseline

2.2

8.3

—

Open-label, randomized multicenter (n = 15) study

CSA (n = 145), FK506 (n = 303)

 

IDDM reversed in 34% FK506 pts

 

PTDM development associated with increasing FK506 levels

 

Scantlebury et al65

3 FBG >150 mg/dL

7

20

NS

Retrospective

 

 

CSA (n = 14), FK506 (n = 20)

 

 

IDDM reversed in 50% FK506 pts with SW and FK506 dosage reduction

 

 

CSA pt (1/14) required only hypoglycemic agent

 

 

Vincenti et al46

Insulin use for >=1 week in pts not receiving insulin at baseline

5

25.4

NS

Open-label, multicenter (n = 5) FK506 dose and concentration ranging trail

 

 

CSA (n = 28), FK506 (n = 92)

 

 

1-year results: IDDM reversed in 29% FK506 pts, single CSA patient still insulin dependent

 

 

Neylan et al16

Insulin use for >30 d in pts with no history of DM

8.3 (B)

36.6 (B)

<0.05

Open-label, randomized, multicenter (n = 19) study

 

 

5.6 (H)

29.4 (H)

<0.05

CSA (n = 121), FK506 (n = 123)

 

 

1.1 (W)

12.2 (W)

<0.05

IDDM reversed (3/15) B and (7/10) W at 2 years with FK506, and in (0/3) B and (0/1) W at 2 years with CSA

 

 

 

 

 

PTDM predictor: race

 

 

Abbreviations: PTDM, posttransplant diabetes mellitus; CSA, cyclosporine; FK506, tacrolimus; DM, diabetes mellitus; FBG, fasting blood glucose; NS, not statistically significant; ID, insulin-dependent; SW, steroid withdrawal; pts, patients; B, black; H, Hispanic; W, white.

 

The first report from the US FK506 Kidney Transplant Study Group presented results for 28 patients randomized to receive CSA and 92 patients to receive tacrolimus and found that 25.4% of the tacrolimus patients versus 5% of the CSA patients not on insulin therapy at baseline required insulin for 7 or more days after transplantation.46

The completed study from this group included 207 patients randomized to receive CSA and 205 patients to receive tacrolimus in 19 centers and used a more stringent criteria for PTDM than the European study of insulin use for greater than 30 days in patients with no prior history of diabetes.15 The investigators found that 19.9% of the patients receiving tacrolimus had developed PTDM compared with 4.0% of those receiving CSA (P < 0.001; Table 4 ). Five of 30 patients on tacrolimus therapy and 1 of 6 patients on CSA therapy stopped insulin use at 1 year. The factors most significantly predictive of the development of PTDM were nonwhite race, steroid dose, and greater tacrolimus levels. In the US trial, tacrolimus levels (12-hour trough) were maintained in the 7- to 15-ng/mL range, whereas CSA levels were maintained in the 135- to 324-ng/mL range. These levels were somewhat greater than those used in the European clinical trial and may explain the greater incidence of PTDM in the US clinical trial.



Table 4. Development of Posttransplant Diabetes Mellitus By Race and Treatment Group

Race

Tacrolimus

Cyclosporine

Patients at Risk (no.)

Patients Who Developed PTDM

Patients at Risk (no.)

Patients Who Developed PTDM

Black

41

15 (36.6%)

36

8 (8.3%)

White

82

10 (12.2%)

87

1 (1.1%)

*Use of insulin for 30 or more consecutive days with <5-day gap, without a prior history of insulin-dependent diabetes mellitus or non–insulin-dependent diabetes mellitus.16


In a subgroup analysis of the US FK506 Kidney Transplant Study, Neylan et al16 reported blacks were at a substantially greater risk for developing PTDM than whites (36.6% of blacks on tacrolimus therapy developed PTDM during the first year posttransplantation compared with only 12.2% of whites). Despite a lower overall incidence of PTDM for patients on CSA therapy, there was still a racial difference with 8.3% of CSA-treated blacks developing PTDM compared with 1.1% of whites. There was no racial difference in the overall achieved drug levels for tacrolimus or CSA during the study. The median time to onset of PTDM was 56 days in the black group and 71 days in the white group. The reversibility of PTDM was also influenced by race because 70% of the white tacrolimus-treated patients initially diagnosed with diabetes no longer required insulin at 2 years versus 20% of the black patients.

FUTURE CLINICAL ISSUES

As pancreas transplantation continues to emerge as a viable alternative for the treatment of juvenile-onset diabetes mellitus, there is particular concern about the development of PTDM and the factors that increase the risk for this complication. Despite the liberation from exogenous insulin in recipients of a successful pancreas transplant, impaired glucose tolerance remains prevalent in this population. The metabolic defects causing this problem include impaired insulin secretion and decreased insulin uptake,77 or possibly insulin resistance caused by systemic drainage of the heterotopic pancreas. Hyperglycemia may be exacerbated by immunosuppressive agents, often leading to a recurrent need for exogenous insulin in some pancreas allograft recipients. The use of tacrolimus after pancreas transplantation has been highly effective in decreasing the incidence of acute rejection; however, it has also been associated with an increased incidence of hyperglycemia and need for exogenous insulin, which may be transient but, in some cases, has required conversion to CSA.77 -79 Further studies are needed to clarify the benefits of tacrolimus versus other agents as immunosuppressive drugs in light of the potential for increased frequency of hyperglycemia and PTDM.

Other new immunosuppressive agents, such as mycophenolate mofetil, have not been reported to show any effect on glycemic control.80 ,81 Rapamycin, a new macrolide antibiotic currently under investigation for its immunosuppressive properties, has not been well studied. Early studies of this drug in experimental animal models suggest it may decrease insulin secretion much in the same way that CSA and tacrolimus can.82 In the European multicenter trial comparing efficacy of rapamycin to CSA in cadaveric renal transplants, rapamycin was found to be associated with a higher incidence of hyperglycemia than CSA. However, the number of patients with new onset PTDM was the same in each group. There is no evidence that biological agents such as antithymocyte globulin or OKT3 monoclonal antibody induce any changes in glycemic control.

Thus, the best controlled clinical trials assessing the effects of immunosuppressant drugs on glycemic tolerance involve CSA or tacrolimus in conjunction with low-dose steroids and azathioprine in kidney transplantation. The question remains whether mycophenolate mofetil as an adjunct to tacrolimus or CSA will allow for lower dosages of each calcineurin inhibitor and a subsequent decrease in the incidence of PTDM.

PATIENT MANAGEMENT CONSIDERATIONS WITH REGARD TO RISK FOR PTDM

On the basis of the previously discussed risks for the development of PTDM, several management considerations are important. First, potential transplant recipients should be profiled to identify those at highest risk. These include patients with a family history of diabetes, abnormal glucose tolerance, blacks, men, and those of greater age. Additionally, it is likely that obese patients are also at much greater risk because of their greater propensity to gain weight in the immediate posttransplantation period. Accordingly, the immunosuppressive regimen must be considered carefully. Both CSA and tacrolimus in conjunction with low doses of corticosteroids increase the risk for PTDM. This risk is somewhat greater with tacrolimus, particularly in Hispanics and blacks. Steroid withdrawal appears to be an effective way to treat CSA-induced PTDM, probably because CSA treatment reduces steroid clearance. Conversely, with tacrolimus, it may be appropriate to reduce the dose of steroids and use other chronic immunosuppressants, such as mycophenolate mofetil. Future clinical trials will need to specifically assess the safety of steroid-sparing regimens with CSA or tacrolimus in conjunction with newer immunosuppressive agents. In either case, given that both drugs in conjunction with low doses of steroids and azathioprine provide similar patient and graft survival rates at 1 year and that PTDM may have a negative impact on both patient and graft survival, appropriate decisions should be made to adjust chronic immunosuppression should PTDM develop.

An effort should be made during the routine laboratory monitoring posttransplantation to carefully assess all patients with recurrent abnormal glucose levels, even if obtained from nonfasting specimens. These are the patients, particularly if they have risk factors for PTDM, who may ultimately develop clinically significant glucose intolerance.

When treating transplant recipients with PTDM, it is important to monitor glycemic control. If the results of the Diabetes Control and Complication Trial20 of patients with type I diabetes and the United Kingdom Prospective Diabetes Study84 of patients with type II diabetes are illustrative of the benefits that may be obtained with regard to rigorous treatment of hyperglycemia in patients who develop diabetes posttransplantation, then efforts to correct abnormalities of glucose tolerance should have a high priority in the transplant population to minimize the secondary vascular complications of diabetes mellitus.

FOOTNOTES

Received September 29, 1998; accepted in revised form December 1, 1998.

Address reprint requests to Matthew R. Weir, MD, Division of Nephrology, University of Maryland Hospital, 22 South Greene St, Baltimore, MD 21201.

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