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Saudi Journal of Kidney Diseases and Transplantation
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Table of Contents   
ORIGINAL ARTICLE  
Year : 2015  |  Volume : 26  |  Issue : 6  |  Page : 1113-1120
Is there a genetic predisposition to new-onset diabetes after kidney transplantation?


1 Madras Medical Mission Hospital, Chennai, India; Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota, USA
2 Madras Medical Mission Hospital, Chennai, India
3 Division of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota, USA
4 Dr. A. Ramachandran Diabetic Hospital, Chennai, India
5 Madras Medical Mission Hospital, Chennai, India; Division of Internal Medicine, Boston University School of Medicine, Boston, Massachusetts, USA

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Date of Web Publication30-Oct-2015
 

   Abstract 

Kidney transplant recipients may develop new-onset diabetes after transplantation (NODAT) and transplant-associated hyperglycemia (TAH) (NODAT or new-onset impaired glucose tolerance-IGT). We studied 251 consecutive renal transplant South Asian recipients for incidence of NODAT and its risk factors between June 2004 and January 2009. Pre-transplant glucose tolerance test (GTT) identified non-diabetics (n = 102, IGT-24, NGT-78) for analysis. Baseline immunosuppression along with either cyclosporine (CsA) (n = 70) or tacrolimus (Tac) (n = 32) was given. Patients underwent GTT 20 days (mean) post-transplant to identify NODAT, normal (N) or IGT. TAH was observed in 40.2% of the patients (40% in CsA and 40.6% in Tac) (P = 0.5). NODAT developed in 13.7% of the patients (12.9% in CsA and 15.6% in Tac) (P = 0.5). Overall, Hepatitis C (P = 0.007), human leukocyte antigen (HLA) B52 (P = 0.03) and lack of HLA A28 (A68/69) (P = 0.03) were associated with TAH. In the Tac group, higher Day 1 dosage (P <0.001), HLA A1 (P = 0.04), B13 (P = 0.03) and lack of DR2 (P = 0.004) increased the risk of TAH. In the CsA group, HLA A10 (P = 0.03), failure of triglyceride (P = 0.001) or low-density lipoprotein (LDL) (P = 0.03) to lower or high-density lipoprotein to rise (P = 0.001), and higher post-transplant LDL (P <0.001) and cholesterol levels (P = 0.02) were associated with NODAT or TAH. Post-transplant fasting plasma glucose on Day 1 had sensitivity-54.5%, specificity-50.1%, positive predictive value-18.1% and negative predictive value-84.8% for detecting NODAT. In conclusion, there is a genetic predisposition to NODAT and TAH in South Asia as seen by the HLA associations, and a predisposition exists to the individual diabetogenic effects of Tac and CsA based on HLA type. This could lead to more careful selection of calcineurin inhibitors based on HLA types in the South Asian population.

How to cite this article:
Reddy YN, Abraham G, Sundaram V, Reddy PP, Mathew M, Nagarajan P, Mehra N, Ramachandran A, Ali AA, Reddy YN. Is there a genetic predisposition to new-onset diabetes after kidney transplantation?. Saudi J Kidney Dis Transpl 2015;26:1113-20

How to cite this URL:
Reddy YN, Abraham G, Sundaram V, Reddy PP, Mathew M, Nagarajan P, Mehra N, Ramachandran A, Ali AA, Reddy YN. Is there a genetic predisposition to new-onset diabetes after kidney transplantation?. Saudi J Kidney Dis Transpl [serial online] 2015 [cited 2020 Jun 5];26:1113-20. Available from: http://www.sjkdt.org/text.asp?2015/26/6/1113/168558

   Introduction Top


New-onset diabetes after transplantation (NODAT) is a well-recognized complication of renal transplantation. [1] Despite the improvement in graft function and survival brought on by the new generation of immunosuppressant medications, [2] these drugs may cause severe morbidity. While their potent immunosuppressant actions permit long-term graft survival, many of these drugs are potentially diabetogenic in addition to their other side-effects. NODAT develops following the use of the calcineurin inhibitors-cyclosporine (CsA) and tacrolimus (Tac), steroids and possibly the mTOR inhibitor, sirolimus. [3]

NODAT, like sporadic diabetes mellitus (DM), is associated with both macrovascular and microvascular complications. The macrovascular complications lead to atherosclerotic disease and an increased risk of cardiovascular mortality along with reduced graft survival. [4],[5],[6],[7] Moreover, the increased survival rates in the recent years for transplant patients increase the risk of microvascular complications of diabetes at an accelerated rate such as microalbuminuria, overt nephropathy, retinopathy and neuropathy.

Impaired glucose tolerance (IGT) after transplant is associated with graft failure and cardiovascular risk in kidney recipients. [4] In the short term also, untreated hyperglycemia is associated with a higher risk of infection and poorer outcome. [8] This emphasizes the need for a thorough understanding of the risk factors in transplant recipients, either inherent or environmental, to be screened in order to prevent the development of IGT or overt DM.

Previous studies looked at steroids and CsA in the development of NODAT in the Indian population. [9],[10] There is a paucity of data with the use of sirolimus and Tac in Indian patients developing IGT or NODAT. Predisposition to DM in the general population has been associated with certain human leukocyte antigen (HLA) types, suggesting a genetic linkage, but the application of this to NODAT patients is less clear, especially in the Indian population.

The aim of this study was to determine the incidence of IGT and NODAT [collectively referred to as transplant-associated hyperglycemia (TAH)] in non-diabetic chronic kidney disease (CKD) patients on maintenance post-transplant immunosuppression with Tac and CsA and to determine the risk factors and the HLA predisposition for the development of the TAH. HLA typing for HLA class I and II were analyzed for possible genetic predisposition to NODAT.


   Methods Top


A prospective analysis of 251 consecutive renal transplant recipients between November 2004 and July 2008 was carried out at a tertiary care hospital in South India after approval by the institutional ethics committee. Exclusion criteria were a history of DM or those with diabetic nephropathy. Those on peritoneal dialysis before transplantation were also excluded due to possible falsely high glucose levels due to the glucose-based peritoneal dialysate. All the patients underwent a standard 75 g oral glucose tolerance test (GTT) both prior to transplantation and within 20 days of transplantation. Both fasting and 2-h glucose values were used for diagnosis. The patients were identified as having either normal glucose tolerance (NGT), IGT or DM as per the American Diabetes Association Criteria. Those with the diagnosis of diabetes established after the pre-transplant GTT were excluded from the analysis, but those with either normal or IGT before the transplantation were included.

A total of 102 patients were identified as nondiabetic (IGT-24, N 78) and were qualified for the analysis, which included 71 males and 31 females. The mean age was 40 years (39 ± 12 years in the CsA group, 41 ± 10 years in the Tac group). Among them, 70 patients received baseline immunosuppression with the microemulsion form of CsA (Neoral) 8 mg/kg in two divided doses and 32 patients received Tac 0.15 mg/kg also in two divided doses. Prednisolone was prescribed at a standard dose (0.5 mg/kg) to both groups. Basiliximab or daclizumab was used in the induction immunosuppression regimen. The other immunosuppressive agents included mycophenolate mofetil (1000 mg twice a day) or sodium salt of mycophenolic acid (720 mg twice a day).

The collected data included viral hepatitis status, dietary habits, pre- and post-transplant body mass index, serum albumin, cytomegalovirus serology, intact parathyroid hormone levels, preand post-transplant serum creatinine and blood urea nitrogen (BUN), hypertension, smoking, alcohol use, pre-operative use of angiotensin-converting enzyme inhibitors, vitamin D and beta blockers. The baseline demography and clinical characteristics are shown in [Table 1]. Table 1}

Total cholesterol, low-density lipoprotein cholesterol (LDL), high-density lipoprotein cholesterol (HDL) and triglyceride (TG) levels were measured before and after transplantation to assess their predictive value in NODAT development. TG was used as a surrogate marker for insulin resistance to determine the pathophysiology of NODAT. [11]{

Based on the post-transplantation GTT, the patients were identified as having either normal glucose tolerance, IGT or NODAT. They were subsequently followed with fasting plasma glucose levels and HbA1c. Treatment was initiated with oral hypoglycemic agents and/or insulin along with lifestyle modification. Oral prednisolone dosage was reduced to 15 mg/day by 45 days in stable functioning allografts and further down to 5-7.5 mg by three months and 2.5 mg/day by six months in about 10% of the patients. The CsA and Tac trough levels were measured as per recommendations to maintain appropriate level intervals and then checked at regular intervals during follow-up.

The two calcineurin inhibitors, CsA and Tac, regimens have never been compared in the Indian population with regard to NODAT and TAH incidence. [10],[11] Drug dosages (from Day 1 to Day 90) and trough levels (from Day 1 to Day 28) were followed. Other possible risk factors were collected and risk factor analysis was performed separately for the CsA and Tac groups.


   Statistical analysis Top


Analysis of variance (ANOVA) was used to determine the differences between the groups with regard to variables with continuous response. Sub-group analysis as needed was performed using the Tukey test to compare the measured variables between the normal, IGT and NODAT groups in patients receiving either CsAor Tac-based regimens. Paired t-test was used to compare the difference between the preand post-transplant levels of lipids and risk factors with continuous response. Analysis of other risk factors with discrete response was performed using the Chi square test. ANOVA was performed for the various HLA types to determine a possible association with the development of NODAT and TAH.

The primary endpoint was considered the development of new-onset IGT or NODAT (collectively referred to as TAH). A negative outcome included those who maintained their pre-transplant normal glucose tolerance or IGT state before and after trans-plantation, and those who reverted back from a pre-transplant uremiainduced IGT state to normal glucose tolerance after transplantation. Sub-group analysis of risk factors was performed separately for the CsA and Tac groups. P-values <0.05 were considered as a significant statistical difference.


   Results Top


Overall, 40.2% of patients had TAH with either new-onset IGT or NODAT. The incidence of NODAT was 13.7% overall as shown in [Table 2], and it was 15.6% in the Tac group and 12.9% in the CsA group, which was not significantly different (P = 0.5). Of all the patients, 59.8% did not show a worsening of their pre-transplant status and either retained their pre-transplant IGT or normal glucose tolerance status, or even reverted back from IGT to normal glucose tolerance after transplantation.
Table 2: Incidence of new-onset diabetes mellitus after transplantation (NODAT) and transplant-associated hyperglycemia (TAH).

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The post-transplant glucose tolerance status of the patients, when they started as either normal glucose tolerance or IGT is shown in [Table 3]. Of the 78 patients who started with normal glucose tolerance before transplantation, 34.6% remained as such after transplantation, 55.1% developed new-onset IGT and 10.3% developed NODAT. There were 24 patients with IGT before transplantation, of which 41.7% had only uremic-induced IGT, which reverted back to normal glucose tolerance after transplantation, 33.3% maintained their IGT status after transplantation without worsening and 25% developed NODAT.
Table 3: Outcome of all patients starting with either normal or impaired glucose tolerance (IGT) before transplantation.

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In the development of TAH in patients on either CsA- or Tac-based regimens, HLA-A28 (A68/69) was found to be protective (P = 0.03, OR = 0.2, 95% CI = 0.04-0.9), while HLA B52 however was associated with TAH (P = 0.03, OR = 2.6, 95% CI = 2.0-3.3). Considering the development of NODAT alone, HLA-B51 (P = 0.01, OR = 7.7, 95% CI = 4.7-13.0) and HLA-B52 (P = 0.007, OR = 14.5, 95% CI = 1.2-172) were associated with this development.

HLA associations in patients on either CsA or Tac regimens were analyzed separately to determine the genetic predisposition to the diabetogenic effects of both drugs, and the results are shown in [Table 4]. Regarding TAH development, HLA-A10 (P = 0.03) was associated with higher risk in the CsA group and HLA-A1 (P = 0.04) and HLA-B13 (P = 0.03) were associated with higher risk in the T group. Interestingly, HLA DR 2, which is well known to be protective for type 1 DM development, [12] was found to be protective against the TAH development as well, but only in patients on Tac (P = 0.004) and not those on CsA regimen (P = 0.7). Other HLA types known to be associated with type 1 DM in the general population, such as HLA DR3, 4, [13] were not found to be significant in patients with TAH (P = 0.3 and P = 0.3, respectively). The HLA associations reported in other studies, such as DR6, [14] were also not shown to be statistically significant (P = 0.7).
Table 4: Human leukocyte antigen types associated with transplant-associated hyperglycemia (TAH).

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Pre-operative Hepatitis C infection was found to be significantly associated with NODAT development (P = 0.007, OR = 14.5, 95% CI = 1.2-172.3). No statistically significant differences were observed between the two subgroups with incidence of Cytomegalovirus infection, usage of pre-operative beta blockers or statins or angiotensin-converting enzyme inhibitors, levels of intact parathyroid hormone or serum albumin, smoking or usage of alcohol, type of induction agent, number of acute rejection treatments, age, diet or gender.

The Tac group with TAH received a mean dose of Tac on Day 1 of 8.4 ± 2.7 mg/day as opposed to a dose of 3.9 ± 1.3 mg/day in those who did not develop TAH, and the mean difference between the two groups was 3.8 mg/day (P <0.001, 95% CI = 2.7-6.4). The trough level of Tac on Day 28 was 12.6 ± 3.5 ng/mL in those who developed IGT versus 8.3 ± 0.7 ng/mL in those who remained with normal glucose tolerance (P = 0.04). Neither dose levels nor trough levels at any time point were found to be statistically different between the TAH and normal patients in the CsA group.

Considering NODAT development alone also showed the Day 1 Tac dosage to be significantly higher in the NODAT group (10.7 ± 1.2 mg/day) compared with those who did not develop NODAT (4.7 ± 2.0 mg/day) with a mean difference of 5.9 mg/day (P < 0.001, 95% CI = 3.2-8.7). Again, patients on CsA did not show any significant trends in the NODAT group with regard to dosage and trough levels.

In the CsA group, there were significantly higher post-transplant cholesterol (P = 0.02) and LDL levels (P <0.001) between those who developed NODAT and those who did not. This change was not seen in either NODAT or TAH patients in the Tac group. Lower LDL (P = 0.02) and TG (P = 0.003) and higher HDL (P <0.001) was observed only in those who did not develop NODAT. No significant changes from pre-to post-transplant levels were observed in the NODAT patients with regard to these variables. No trends were observed in the change of lipid levels in the Tac group.


   Discussion Top


The incidence of NODAT has been shown in the DIRECT trial [15] to be higher in patients receiving Tac than CsA. Our study suggests that the incidence of NODAT and TAH in South Asia appears similar irrespective of whether CsA or Tac was used for immunosuppression. Also interesting was the observation that 41.7% of patients with IGT before transplantation reverted back to normal glucose tolerance after their transplantation possibly from resolution of uremic-induced insulin resistance.

As DM, there appears to be a significant genetic predisposition to NODAT (HLA-B51 and HLA-B52) and TAH (HLA-B52 and lack of HLA-A28) development in our population with possible individual genetic susceptibility to the individual diabetogenic effect of CsA and Tac. In addition, in the patients receiving CsA, HLA-A10 was associated with TAH, while in the patients receiving Tac, HLA-A1, B13 and lack of DR2 were associated with TAH. Both type 1 and type 2 DM have a well-defined genetic predisposition in the general population with a stronger genetic component in type 2 patients. In the general population, HLA DR 2 is believed to be protective from type 1 DM. The observation that HLA DR2 was associated with a lower risk of TAH in patients on Tac possibly underlies a common pathogenetic mechanism of decreased insulin secretion between type 1 DM and Tac-induced TAH. This does not appear to play a role in the CsA-induced TAH. The post-transplant TG level (as a measure of insulin resistance) [11] was not significantly different between the TAH patients and those who did not develop TAH in the Tac group, nor did the TG level show any change from preto post-transplantation levels in this group. This further supports our concept that TAH development in the Tac group was predominantly due to decreased insulin secretion and not due to insulin resistance. [16],[17]

On the contrary, insulin resistance (as measured by the TG levels) appeared to play a major role in the NODAT and TAH development in the CsA group; the patients who developed NODAT did not show any significant changes in the TG, LDL or HDL levels from preto post-transplantation. On the other hand, lower TG or LDL after transplantation was observed in the patients who did not develop TAH and could represent a sign of lower risk of TAH. This likely underscores the role of insulin resistance in the CsA-induced NODAT and TAH, with lowering of TG (insulin resistance) being associated with lower risk of NODAT and TAH. [18],[19],[20]

The pathogenesis of calcineurin inhibitor-induced NODAT is believed to be due to both impaired insulin release, as a result of toxic effects on the beta cells of the pancreas, as well as insulin resistance, but the relative importance of these two mechanisms is not well understood, with conflicting results from numerous studies. [21],[22],[23] Our study suggests that insulin resistance is the main determinant of the CsA-induced NODAT, whereas decreased insulin release is possibly the main determinant of the Tac-induced NODAT.

Our study again showed the poor sensitivity, specificity and positive predictive value of the fasting plasma glucose over the Oral Glucose Tolerance Test (OGTT). [1],[24],[25] The fasting blood glucose appeared to have a moderate negative predictive value at 84.8%. However, in view of the reduced graft survival and complications of NODAT, and the fact that early detection of patients and prompt treatment with lifestyle modification and medication has been shown to decrease complications from the disease; [26],[27] we recommend routine OGTT to be carried out on all patients in the transplant settings to detect disease as early as possible.

In our study, the dose of Tac on Day 1 was highly predictive of the development of TAH and NODAT, with significantly higher levels occurring with those who developed TAH and NODAT, and this observation coincides with previous studies. [17],[28] In addition, the Tac trough level on Day 28 was found to be significantly higher between those with IGT compared with normal glucose tolerance. These represent time points at which lowering of Tac to the lowest effective level may prevent NODAT or TAH. However, the trough levels and doses of CsA were not found to be significant at all times for the development of NODAT or TAH. Hepatitis C seropositivity has been shown to be a risk factor for DM in general and for NODAT in particular. [29] Our study again found Hepatitis C to be significantly associated with the development of NODAT.

In applying this study to the general population, certain limitations of the study should be addressed. Data on C-peptide and insulin levels in patients would provide further insight into the pathophysiology of NODAT in both groups of patients. The small number of patients in the subgroup analysis performed for the HLA associations should lead to cautious interpretation of these findings; they should be currently viewed as only hypothesis generating and require additional studies. There is much variation in the current literature regarding HLA associations with NODAT, possibly reflecting a racial or geographical variation in susceptibility.

In conclusion, NODAT appears to be a significant entity in South Asia, with 40.2% of nondiabetic transplant patients developing a new onset of TAH. There was no statistically significant difference in NODAT incidence between patients receiving CsA and Tac. The HLA types associated with NODAT and TAH show that there is a significant genetic component to TAH susceptibility in South Asia.

Conflict of interest: None declared.

 
   References Top

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Cosio FG, Pesavento TE, Kim S, Osei K, Henry M, Ferguson RM. Patient survival after renal transplantation: IV. Impact of post-transplant diabetes. Kidney Int 2002;62:1440-6.  Back to cited text no. 6
    
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González-Posada JM, Hernández D, Genís BB, et al. Increased cardiovascular risk profile and mortality in kidney allograft recipients with post-transplant diabetes mellitus in Spain. Clin Transplant 2006;20:650-8.  Back to cited text no. 7
    
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Saleem TF, Cunningham KE, Hollenbeak CS, Alfrey EJ, Gabbay RA. Development of diabetes mellitus post-renal transplantation is associated with poor short-term clinical outcomes. Transplant Proc 2003;35:2916-8.  Back to cited text no. 8
    
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Saxena S, Dash SC, Guleria S, et al. Post transplant diabetes mellitus in live related renal allograft recipients: A single centre experience. J Assoc Physicians India 1996;44:472, 477-9.  Back to cited text no. 9
    
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Snehalatha C, Satyavani K, Sivasankari S, Vijay V, Ramachandran A. Serum triglycerides as a marker of insulin resistance in non-diabetic urban Indians. Diabetes Res Clin Pract 2005; 69:205-6.  Back to cited text no. 10
[PUBMED]    
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Mathew JT, Rao M, Job V, Ratnaswamy S, Jacob CK. Post-transplant hyperglycaemia: A study of risk factors. Nephrol Dial Transplant 2003;18:164-71.  Back to cited text no. 11
    
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Lernmark A. Type 1 diabetes. Clin Chem 1999; 45:1331-8.  Back to cited text no. 12
    
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Huang HS, Huang MJ, Huang CC. Assessment of the association of HLA-DR 3/4 heterozygotes with diabetes mellitus and non-diabetic diseases. J Formos Med Assoc 1992;91:233-6.  Back to cited text no. 13
    
14.
Nafar M, Pour-Reza-Gholi F, Amouzegar A, et al. Is HLA-DR6 a protective factor against posttransplantation diabetes mellitus? Transplant Proc 2005;37:3098-100.  Back to cited text no. 14
    
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Vincenti F, Friman S, Scheuermann E, et al. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7:1506-14.  Back to cited text no. 15
    
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Radu RG, Fujimoto S, Mukai E, et al. Tacrolimus suppresses glucose-induced insulin release from pancreatic islets by reducing glucokinase activity. Am J Physiol Endocrinol Metab 2005;288:E365-71.  Back to cited text no. 16
    
17.
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18.
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Lo A. Immunosuppression and metabolic syndrome in renal transplant recipients. Metab Syndr Relat Disord 2004;2:263-73.  Back to cited text no. 19
    
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Kang JS, Kim DS, Lee CH, et al. Effect of cyclosporine on glucose tolerance in streptozotocin-diabetic rats: Cyclosporine may deteriorate insulin sensitivity. Transplant Proc 1999;31:2150-3.  Back to cited text no. 20
    
21.
Wyzgal J, Paczek L, Sanko-Resmer J, et al. Insulin resistance in kidney allograft recipients treated with calcineurin inhibitors. Ann Transplant 2007;12:26-9.  Back to cited text no. 21
    
22.
Hagen M, Hjelmesaeth J, Jenssen T, Morkrid L, Hartmann A. A 6-year prospective study on new onset diabetes mellitus, insulin release and insulin sensitivity in renal transplant recipients. Nephrol Dial Transplant 2003;18:2154-9.  Back to cited text no. 22
    
23.
Nam JH, Mun JI, Kim SI, et al. beta-Cell dysfunction rather than insulin resistance is the main contributing factor for the development of postrenal transplantation diabetes mellitus. Transplantation 2001;71:1417-23.  Back to cited text no. 23
    
24.
Sharif A, Moore RH, Baboolal K. The use of oral glucose tolerance tests to risk stratify for new-onset diabetes after transplantation: An underdiagnosed phenomenon. Transplantation 2006;82:1667-72.  Back to cited text no. 24
    
25.
Ramesh Prasad GV, Huang M, Bandukwala F, et al. Pre-transplantation glucose testing for predicting new-onset diabetes mellitus after renal transplantation. Clin Nephrol 2009;71: 140-6.  Back to cited text no. 25
    
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28.
Rodrigo E, de Cos MA, Fernández-Fresnedo G, et al. Higher initial tacrolimus blood levels and concentration-dose ratios in kidney transplant recipients who develop diabetes mellitus. Transplant Proc 2005;37:3819-20.  Back to cited text no. 28
    
29.
Fabrizi F, Martin P, Dixit V, Bunnapradist S, Kanwal F, Dulai G. Post-transplant diabetes mellitus and HCV seropositive status after renal transplantation: meta-analysis of clinical studies. Am J Transplant 2005;5:2433-40.  Back to cited text no. 29
    

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Correspondence Address:
Yogesh N. V. Reddy
Division of Cardiovascular Diseases Mayo Clinic, Rochester, MN, 55905 USA

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DOI: 10.4103/1319-2442.168558

PMID: 26586047

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