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New-Onset Diabetes after Kidney Transplantation: Risk Factors

Nephrology Service, University of Cantabria, Santander, Spain

Address correspondence to: Dr. Manuel Arias, Nephrology service, University of Cantabria, Avda. Valdecilla s/n 39008, Santander, Spain. Phone: +34942202738; Fax: +34942320415; E-mail: nefarm{at}humv.es

	Abstract

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 
New-onset diabetes after transplantation (NODAT) contributes to the risk for cardiovascular disease and infection, reducing graft and patient survival. For improvement of the outcome of kidney transplant recipients, it is of great interest to know precisely the risk factors that contribute to NODAT development. Nonmodifiable risk factors for development of NODAT are age, race, genetic background, family history of diabetes, and previous glucose intolerance. Modifiable risk factors are obesity and overweight, hepatitis C virus and cytomegalovirus infections, and immunosuppressive drugs. Both steroids and calcineurin inhibitors influence the appearance of NODAT, whereas the role of sirolimus in glucose metabolism currently is controversial.

	Introduction

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 
The two major causes of kidney transplant loss are chronic allograft nephropathy and death with a functioning kidney. It is widely known that renal transplant recipients are at high risk for cardiovascular disease (CVD). Both pretransplantation diabetes and new-onset diabetes after transplantation (NODAT) contribute to the risk for CVD and infection, reducing graft and patient survival (1). Although some studies have reported similar long-term survival in patients who develop NODAT than in control subjects without diabetes (2), a majority of reports indicate that NODAT is associated with reduced patient survival (3,4) and with CVD (4–6). Prospective single-center studies that used the 2003 International Consensus definition of NODAT showed that NODAT increases the risk for long-term cardiovascular adverse events between 1.34 and 3.27 times as compared with patients without diabetes (5,6). In addition, large, retrospective registries have concluded that NODAT is a strong, independent predictor of global mortality, graft failure, and death-censored graft failure (3). For reduction of CVD and improve the outcome for kidney transplant recipients, it is of great interest to know precisely the risk factors that contribute to NODAT development and maintenance. In a recent report, Cosio et al. (7) demonstrated that patients who resolved NODAT showed the same incidence of cardiovascular events as euglycemic patients. In this review, we analyze the current knowledge about NODAT risk factors (Table 1).

	Nonmodifiable Risk Factors

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

Older age is the strongest and most consistent risk factor for NODAT in kidney transplantation and is reported in the majority of studies (3,7,8,11–16). In a study that included 2078 allograft recipients, Cosio et al. (10) showed that those who were older than 45 were 2.9 times more likely to develop diabetes. In addition, the rate of increase in NODAT cases after the first 6 mo is significantly faster in older than in younger individuals. Data from the US Renal Data System (USRDS) showed that first kidney transplant recipients who were between 45 and 59 yr had a relative risk (RR) for NODAT of 1.9 (95% confidence interval [CI] 1.73 to 2.09; P < 0.0001), whereas patients who were 60 yr had a risk of 2.6 (95% CI 2.32 to 2.92; P < 0.0001) (3). Age increased the risk for development of diabetes 1.5-fold for every 10-yr increase in age (15).

Similar to the higher incidence of type 2 diabetes and insulin resistance in that nontransplant population, black and Hispanic populations have a greater risk for developing NODAT than do white individual (3,9,10,11,14,16,17). In a single-center study that included 122 kidney transplant patients, black recipients had roughly twice the risk for developing NODAT as defined by 2003 consensus criteria (17). Data from the USRDS found an RR of NODAT of 1.68 (95% CI 1.52 to 1.85; P < 0.0001) for black patients and of 1.35 (95% CI 1.19 to 1.54; P < 0.0001) for Hispanic patients (3). The differences in patients of different ethnicity may reflect variations in the pharmacokinetics and diabetogenic effects of immunosuppressive agents (1).

There is conflicting evidence regarding the importance of family history of diabetes and impaired glucose tolerance before transplantation (11). Individuals with a history of diabetes among first-degree relatives should be identified to prevent the development of NODAT. Some reports have detected that a family history of diabetes increases up to seven times the risk for NODAT (9,18).

Data are scarce with respect to genetic background. Results from studies that analyzed the association between HLA phenotypes and NODAT were contradictory. Hence, HLA phenotype cannot be considered as a reliable risk factor for NODAT (1). In the general population, several genetic polymorphisms have been considered as contributing to diabetes. Some of these polymorphisms are related to insulin secretion (vitamin D receptor and uncoupling protein 2 genes), and some of them are related to insulin sensitivity (peroxisome proliferator–activated receptor-, angiotensin-converting enzyme, and adiponectin genes). A study that included 70 kidney transplant recipients found that patients with vitamin D receptor TaqI t allele were at a higher risk (odds ratio 7.05; P = 0.048) for NODAT. In this report, none of the other studied polymorphisms, including those that were related to tacrolimus pharmacokinetics, influenced the appearance of NODAT (8).

Abnormal glucose regulation before transplantation may increase the risk for development of NODAT, but it is not a risk factor in all reports (1,17). The presence of other components of metabolic syndrome, such as abdominal perimeter, hypertriglyceridemia, and hypertension, may be useful predictors of NODAT, although their precise role is difficult to define (1). In a recent report, Cosio et al. (7) showed that elevated triglyceride and glucose levels before transplantation were related to increasing risk for NODAT. Among patients with pretransplantation fasting plasma glucose (FPG) >100 mg/dl, at 1 yr, 70% had FPG >100 mg/dl and 27% had FPG >126 mg/dl. The use of American Diabetes Association criteria before transplantation helps in the identification of patients who are at a higher risk for developing NODAT in a simple way, without performing an oral glucose tolerance test.

	Overweight, Obesity, and Weight Gain

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 
Obesity is a potentially modifiable risk factor. Body weight and body mass index (BMI) have been shown to be associated with the development of NODAT in most studies (2,3,7,8,14,19,20), although not significantly in all reports (9,11,15,17,18). Data from the USRDS revealed that obese patients (BMI 30 kg/m²) have an RR for NODAT of 1.73 (95% CI 1.57 to 1.90; P < 0.0001), being, along with age, one of the most consistent risk factors (3). NODAT risk increases linearly for every 1 kg above 45 kg (14). As well as obesity, overweight patients (BMI 25 and <30 kg/m²) also are at risk for developing NODAT (13). In overweight nontransplantation patients with impaired glucose tolerance (IGT), lifestyle modification has been shown to reduce the risk for type 2 diabetes after 4 yr, from 23% in the control group to 11% in the intervention group (21). Extending these findings to kidney transplantation, lifestyle modification while on a waiting list may reduce the incidence of NODAT.

Although many patients experience considerable weight gain during the first year after transplantation, the incidence of NODAT did not correlate significantly with the amount of weight gain that the patient had during the first posttransplantation year (10,13,15). Influence of weight gain over NODAT can become more evident in long-term studies than in 1-yr studies. Because weight gain is a risk factor for development of an insulin-resistant state and type 2 diabetes in the general population, it seems logical to insist that transplant recipients maintain a normal weight.

	Viral Infection

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 
The hypothesis that viral infections may provoke type 1 diabetes in genetically predisposed individuals is widely accepted. Some studies have indicated that viral infections also may increase the risk for type 2 diabetes. A higher prevalence of type 2 diabetes has been reported with hepatitis C virus (HCV) infection in the general population (22). HCV infection is a significant comorbid condition in kidney and liver transplant recipients and is associated with an increased risk for both graft failure and mortality (1). Data from single-center, limited-size, observational studies showed conflicting results about the relationship between NODAT and HCV status (23). However, this relationship is more evident in the USRDS registry. One-year incidence of NODAT in HCV-positive patients at transplantation was 25.6% compared with HCV-negative patients (15.4%; P < 0.0001) (3). A meta-analysis of clinical studies that involved 2502 kidney recipients concluded that the adjusted odds ratio for NODAT was 3.97 (95% CI 1.83 to 8.61) (23). HCV infection is a potentially modifiable risk factor for NODAT after kidney transplantation. Successful pretransplantation treatment of HCV potentially could reduce the incidence of NODAT.

Cytomegalovirus (CMV) infection has been associated with type 1 diabetes. Hjelmesaeth et al. (22) speculated that CMV also increases the risk for NODAT. They found that kidney recipients who had symptomatic or asymptomatic CMV disease were at higher risk for developing NODAT. They reported that the incidence of NODAT was 6% in a control group and 26% in the group with asymptomatic CMV infection as defined by monitoring CMV pp65 protein in blood. These results have not been confirmed by other groups (8,15,17). The possibility of using valacyclovir, ganciclovir, or valganciclovir to prevent CMV infection and subsequent NODAT remains to be assessed in future studies (22).

	Immunosuppressive Drugs

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 
Steroids
Evidence suggests that immunosuppressive drugs account for 74% of the risk for NODAT development (11). The association between corticosteroids and NODAT is established clearly and is related to cumulative dosages and therapy duration (1,14). In the initial years of transplantation, higher dosages of corticosteroids were used and the incidence of NODAT was reported to be as high as 46%. The progressive reduction in corticosteroid dosages has led to a parallel reduction in NODAT incidence (24). In the prospective study by Boots et al. (25), glucose metabolism improved after corticosteroid withdrawal of 10 mg of prednisolone by decreasing insulin resistance. Further dosage reduction under 5 mg/d has not been related to a clear improvement in glucose metabolism (26). As a result of the current lower dosages, several studies did not find any influence of cumulative corticosteroid dosages on the appearance of NODAT (8,11,13,15,17,19,20). Some of these have shown that patients who receive steroid pulses as a result of acute rejection are at higher risk (11,15,19).

Large, prospective, multicenter trials also have shown the importance of therapy duration. Whereas steroid withdrawal at 3 mo did not reduce the incidence of NODAT significantly, corticosteroid avoidance from the first day resulted in a significant reduction of NODAT (5.4 versus 0.4%; P = 0.003) (27,28). Although it is known that the lower the corticosteroid dosages, the lower the long-term incidence of diabetes, corticosteroid withdrawal or dosage reduction must be balanced against the risk for acute rejection. A 5-yr prospective trial is ongoing to compare steroid cessation at day 8 versus long-term maintenance therapy in renal transplant recipients (29).

Calcineurin Inhibitors
Although cyclosporine therapy allowed a reduction in steroid dosages with the subsequent reduction of NODAT incidence, calcineurin inhibitors (CNI) also have been associated with glucose metabolism impairment (1). Clinical studies indicate that tacrolimus is associated with a higher risk for IGT and NODAT than is cyclosporine. The USRDS showed that the risk for NODAT was 53% greater in patients who received tacrolimus, and the rate of NODAT diagnosis during the second year also was greater (3,16). Retrospective studies and randomized, controlled trials have found that the incidence of NODAT was higher among patients who were treated with tacrolimus compared with cyclosporine (3,11,12,15,24). Several meta-analyses have reviewed this issue systematically, with similar results (11,24,30). A recently reported review that involved 4102 renal transplant recipients found that the RR for NODAT at 1 and 3 yr were 1.86 (95% CI 1.11 to 3.09) and 3.86 (95% CI 2.01 to 7.41) higher with tacrolimus, respectively (30). A similar NODAT risk also was reported in nonrenal transplants (24). The progressive reduction in target tacrolimus blood levels and the use of microemulsion cyclosporine, which seems more diabetogenic than the original cyclosporine formulation, have led to a reduction in the differences in the incidence of NODAT between tacrolimus and cyclosporine (10,11,24,30).

It is not defined whether the effect of CNI on glucose metabolism is dosage dependent. The trough levels of tacrolimus and cyclosporine have been reported to be associated as well as not associated with NODAT (11,12). Gourishankar et al. (15) found no relationship between cyclosporine and tacrolimus trough blood levels at any time point (month 1, month 6, year 1, and year 5) and NODAT. Similar results were reported by Romagnoli et al. (20). Cyclosporine and tacrolimus trough blood levels at discharge; 3 and 6 mo; and 1, 3, and 5 yr were not related to the appearance of NODAT. However, early posttransplantation levels are associated with the development of NODAT. Maes et al. (19) reported that the number of tacrolimus trough levels >15 ng/ml during the first month determined the development of NODAT. We found similar results in 76 kidney recipients. The appearance of a first tacrolimus level >20 ng/ml was associated with a NODAT RR of 9.33 (95% CI 2.28 to 38.03; P = 0.001), after adjusting for age and BMI. Nearly 81% of patients with NODAT showed a first level >20 ng/ml, whereas only 22% of patients without NODAT had such a high first level. After this point, we did not find any differences in levels between patients with and without NODAT. By contrast, patients with NODAT maintained higher tacrolimus concentration-dosage ratios for 6 mo, which can be explained by differences in drug metabolism (13).

Progressive reduction in CNI target levels have led to a lower incidence of NODAT (11,19,30). Tacrolimus concentrations of 10 ng/ml are associated with both a maximal benefit on graft survival and a minimal risk for NODAT (30). This finding is in accordance with several studies that analyzed the glucose metabolism by glucose tolerance tests. After the start of tacrolimus, there was a 39% reduction in the insulin sensitivity index. This index was inversely correlated with the tacrolimus trough level. No patients with tacrolimus trough levels <15 ng/ml showed an abnormal index (31). A 33% tacrolimus level reduction resulted in a 36% improvement in pancreatic cell secretion capacity (25). Because glucose metabolism depends more on tacrolimus area under the curve and trough level than on peak level, it seems that the change to the new modified release formulation of tacrolimus (MR4) will not alter the current knowledge about the NODAT–tacrolimus relationship (32).

Tacrolimus is associated with a higher rate of NODAT but not with a reduced risk for graft failure (3). According to Webster et al. (30), treating 100 recipients with tacrolimus instead of cyclosporine for the first year after transplantation prevents 12 patients from having acute rejection and two from losing their graft but makes an extra five patients develop insulin-dependent diabetes. To improve glucose metabolism, it seems more reasonable to convert to a CNI-free regimen, although there is some risk for having an acute rejection episode, or to reduce tacrolimus dosages (33). A reduction in blood levels of CNI may help to diminish the risk for NODAT.

Other Immunosuppressive Drugs
The use of azathioprine and mycophenolate mofetil has been associated with a lower risk for NODAT, probably because of the possibility of reducing dosages of other, more diabetogenic immunosuppressive agents. Patients who are on azathioprine and mycophenolate mofetil therapy have a 16 and 22% lower incidence of NODAT, respectively, although this point has not been confirmed in a meta-analysis (3,30). The role of sirolimus in glucose metabolism currently is controversial. Initial trials have not shown an increase in diabetes rate when sirolimus was added or compared with cyclosporine (reviewed in reference [34]). Retrospective analysis did not find any influence of sirolimus in the incidence of NODAT (15) or find any improvement of glucose metabolism (35). A higher incidence of NODAT in black patients who received sirolimus in combination with tacrolimus suggests the possibility that sirolimus impaired glucose metabolism (36). Teutonico et al. (34) performed a prospective study in 26 kidney transplant recipients who were converted from cyclosporine to sirolimus and 15 who were treated with tacrolimus plus sirolimus and discontinued tacrolimus. The switch to sirolimus was associated with a 30% increased incidence of IGT (from 31.7 to 41.5%) and the development of four cases of NODAT, as a result of a defect in the compensatory cell response and a fall of insulin sensitivity. In a similar way, we performed a 3-mo prospective study in 35 patients who switched from CNI to sirolimus. Whereas at baseline four (11.4%) patients had impaired fasting glucose, nine (25.7%; P = 0.025) showed impaired fasting glucose at month 1, 10 (28.6%; P = 0.034) at month 2, and nine (25.7%; P = 0.025) at month 3 (37). Although more studies are necessary to confirm these data, it seems unlikely that sirolimus would improve glucose metabolism after withdrawal.

	Conclusion

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 
Nonmodifiable risk factors for development of NODAT are age, race, genetic background, family history of diabetes, and previous glucose intolerance. Modifiable risk factors are obesity and overweight, HCV and CMV infections, and immunosuppressive drugs. Immunosuppressive drugs account for 74% of the risk for NODAT development. Steroid dosages must be reduced to 5 mg/d as early as possible or avoided completely. Because of the higher diabetogenic activity of tacrolimus, it could be reasonable to avoid or to reduce dosages in patients with several associated risk factors, although this approach has yet to be demonstrated. Some evidence suggests that tacrolimus target levels must be maintained under 10 ng/ml. Switching to sirolimus does not seem to improve glucose metabolism.

	References

Top Abstract Introduction Nonmodifiable Risk Factors Overweight, Obesity, and Weight... Viral Infection Immunosuppressive Drugs Conclusion References

 

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