Objectives: New-onset diabetes mellitus after transplant is a common complication in renal allograft recipients. Recently, a high prevalence of diabetes mellitus has been reported in patients with chronic hepatitis C virus. The association between hepatitis C and diabetes mellitus is well demonstrated in the general population, but some controversy still exists. This work aimed to study the effect of pretransplant hepatitis C virus on the development of new-onset diabetes mellitus after transplant in Egyptian living-donor renal allotransplant recipients.

Materials and Methods: This retrospective single center study included 913 kidney transplant recipients who were transplanted at Mansoura Urology and Nephrology Center between 2000 and 2010. The patients were divided into 4 groups according to their hepatitis C virus serology and diabetic status.

Results: Pretransplant dialysis duration and number of blood transfusion units were statistically significant among both viremic and nonviremic groups. With respect to induction therapy, a highly statistical significance was observed between the 4 groups regarding presence and type of adjuvant therapy (P < .001). With respect to maintenance immunosuppression, high statistically significant results were observed regarding steroid and rapamycin between the 4 groups (P < .001) with lower significance regarding mycophenolate mofetil (P = .04) but no significance regarding azathioprine, cyclosporine, or tacrolimus therapy. Incidence of new-onset diabetes mellitus after transplant was statistically higher in the viremic than nonviremic group (P < .001).

Conclusions: There was a positive correlation between incidence of new-onset diabetes mellitus after transplant and positive pretransplant hepatitis C virus status.

Key words : Kidney, Viremic state, Immunosuppression

Introduction

With improvements in patient and graft survival after transplant in the last decade, increasing attention has been placed on nonimmunologic outcomes that contribute to patient morbidity and mortality. Among the leading causes of death in renal transplant recipients are cardiovascular disease and infection. New-onset of diabetes mellitus (DM) after transplant (NODAT) has been linked to higher rates of cardiovascular disease and infection and is a major cause of morbidity and mortality.¹ The NODAT is a common complication in renal allograft recipients.

Recently, a high prevalence of DM has been reported in patients with chronic hepatitis C virus (HCV) infection with or without liver cirrhosis, liver transplant recipients, and renal transplant patients. However, the association is controversial. Among several factors implicated in the development of posttransplant DM are the diabetogenic effects of immunosuppressive drugs, such as steroids and calcineurin inhibitors, and genetic predisposition.² Infection with HCV is 1 of the most important causes of cirrhosis and hepatocellular carcinoma and has a large effect on public health worldwide. The HCV is hepatotropic and lymphotropic. Replication of HCV in diseased extrahepatic organs and tissues may trigger latent autoimmunity or induce autoimmune disorders and cause liver injury.³

The association between type 2 DM and chronic HCV infection was first reported in 1994, when it was observed that the prevalence of type 2 DM was significantly higher in patients with HCV-related cirrhosis than patients with cirrhosis resulting from other liver diseases.⁴

Materials and Methods

Patients
This work was performed all patients with end-stage renal disease who were transplanted at Mansoura Urology and Nephrology Center from the beginning of January 2000 to the end of December 2010. The data of the patients were retrospectively reviewed. Patients who were negative for hepatitis B surface antigen and living patients with a functioning graft for ≥ 6 months posttransplant were included in the study. Patients were excluded from the study when they were hepatitis B surface antigen-positive (acquired the infection either pretransplant or posttransplant) (17 patients), died or had graft failure within the first 6 months posttransplant (22 patients), were lost to follow-up (56 patients), had pretransplant DM (11 patients), had DM risk factors such as family history (59 patients), and non-Egyptian renal transplant recipients (35 patients). After excluding the patients who had not fulfilled the inclusion criteria, 913 patients were included. Our patients were divided into 4 groups according to their DM and HCV antibody serologic status: group 1 patients (511 patients) were HCV negative without posttransplant DM; group 2 patients (87 patients) were HCV negative with posttransplant DM; group 3 patients (230 patients) were HCV positive without posttransplant DM; and group 4 patients (85 patients) were HCV positive with posttransplant DM.

The study protocol was approved by the institutional review board at The Urology and Nephrology Center (Mansoura, Egypt), complied with the Declaration of Helsinki and a written informed consent was obtained from all the study participants.

Pretransplant evaluation
All patients were evaluated before kidney transplant. Thorough history was taken with special emphasis on type and duration of dialysis, number of blood transfusions, any procedure that could lead to HCV transmission, original kidney disease, DM symptoms (include polyuria, polydipsia, and unexplained weight loss), family history of DM, history of acute diabetic complications, and thorough clinical examination with special attention to liver and spleen examination.

Posttransplant evaluation
After kidney transplant, our recipients were primarily immunosuppressed according to standardized pro-tocols including different immunosuppressive drugs such as steroids, tacrolimus, cyclosporine, myco-
phenolate mofetil, sirolimus, and azathioprine. Graft function, patient survival, and graft survival were assessed.

Monitoring for new-onset of diabetes mellitus after transplant
All patients had blood glucose measurements perfor-med routinely during the initial hospitalization at the time of transplant. Blood glucose measurements were made every 12 hours for the first 3 days after transplant. Thereafter, blood glucose levels were measured daily while the recipient was an inpatient, twice weekly for the first posttransplant month as an outpatient, weekly for the second posttransplant month, and whenever patients had routine chemistry studies. The NODAT was diagnosed according to American Diabetes Association guidelines (2011).⁵ Diagnostic criteria included (1) symptoms of DM plus random plasma glucose ≥ 200 mg/dL (11.1 mmol/L), hemoglobin A1c ≥ 6.5% (48 mmol/mol) (symptoms included polyuria, polydipsia, and unexplained weight loss); (2) fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L) (fasting was defined as no caloric intake for at least 8 hours); and (3) 2-hour plasma glucose ≥ 200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test.⁵

Additional data collected
Additional data collected included recipient age and sex, donor age and sex, donor and recipient relationship, cause of end-stage renal disease, same or different compatible blood group, human leukocyte antigen (HLA) types (HLA-A, B, and DR) and number of matches and mismatches, viral profile (hepatitis B surface antigen and antibody, HCV antibody, cytomegalovirus immunoglobulin M, and human immunodeficiency virus 1 and 2 antibody), duration of dialysis, and pretransplant blood transfusion.

Statistical analyses
The findings were recorded, tabulated, and analyzed by (SPSS for Windows, release 10 SPSS Inc. Chicago, III, USA, 1993). Analysis of variance was used to compare continuous data between the 4 groups. Categorical data were compared using chi-square test. Graft and patient survival were computed using Kaplan-Meier method. A value of  P ≤ .05 was considered statistically significant.

Results

Demographic data of the recipients and donors
In this cohort study, patients who developed NODAT were significantly older in both diabetic groups (group 2 and 4), the mean recipient age in years at transplant procedure time was statistically significant (P < .001); and the age interval between 35-50 years had the highest percentage of NODAT development. Consanguinity had statistical signifi-cance with higher percentage of unrelated donors in both diabetic groups (P < .001). There was no significance regarding the sex of both recipient and donor (Table 1). Body mass index (BMI) showed a statistical significance (P = .04); BMI < 30 kg/m² was associated with higher incidence of NODAT (Table 1). There was a statistical significance regarding history of pretransplant dialysis, and HCV antibody-positive groups had the highest percentage. The number of blood transfusion units had a statistical significance (P < .001) (Table 1).

Pretransplant medical disorders and immunologic evaluation
There was a statistical significance between the 4 groups in pretransplant schistosomiasis and hyper-tension, with the highest percentage in the HCV antibody-positive groups (schistosomiasis, P < .001; hypertension, P = .02) but no significance regarding original kidney disease (P = .444) (Table 1). There was a higher percentage of HLA class I (2 match; P < .001) and HLA class II (DR, 1 match, P = .04) in the 4 groups with high statistical signifi-cance. The HLA had not been done with some transplant recipients who received their transplanted kidney from a parent or after being sure that DR matching was at least 50%, but there was no significance regarding blood group compatibility (P = .97) (Table 2).

Adjuvant therapy and immunosuppression
A highly statistical significance was observed between the 4 groups regarding presence and type of adjuvant therapy (P < .001), and basiliximab induction had the highest percentage (Table 3). There was a statistical significance in the total dose of steroids in the first 3 months between the different groups (P = .04) (Table 4). Regarding steroid and sirolimus therapy between the 4 groups, high statis-tically significant differences were observed (P < .001), with lower significance regarding mycophenolate mofetil (P = .04) and no significance regarding azathioprine, cyclosporine, or tacrolimus (Table 5).

Posttransplant liver status, graft function, and survival
The posttransplant liver status judged by alanine aminotransferase level showed no statistically significance (P = .08) (Table 6). Mean serum creatinine and creatinine clearance at last follow-up was highly significant between the 4 groups (P ≤ .001). A statistical significance was observed regarding the condition at last follow-up (P < .001), and living with a functioning graft had the highest percentage in the 4 conditions (P < .001) (Table 7).

All factors that had a significant value in the univariate analysis between the 4 groups were studied with multivariate analysis, and only recipient age, total dose of steroid in the first 3 months posttransplant, time to diuresis, sirolimus for primary immunosuppression, and adjuvant therapy were significant on multivariate analysis (Table 8).

The percentage of development of NODAT was greater in the HCV-positive group (27%) than HCV negative group (14.5%) with high significance (P < .001) (Figure 1). The 4 groups had statistically significant differences in graft survival (P = .012) (Figure 2).

Discussion

The NODAT also is known as posttransplant DM, transplant-associated hyperglycemia, or new-onset DM, and is a common metabolic complication post-transplant. The incidence ranges from 2% to 53%, reflecting wide variations in the definition of  the disorder, population, and immunosuppressive regimen.⁶

In our study, frequency of development of DM was greater in the HCV-positive (27%) than HCV-negative group (14.5%) (P < .001). This finding was similar to results reported by other investigators.^7-9 In 1 study, HCV-positive recipients had a significantly lower insulin sensitivity (3.0 ± 2.1min−1.μU.mL−1.104) than HCV-negative recipients (4.9 ± 3.0 min−1. μU.mL−1.104; P = .02), but insulin secretion and hepatic insulin uptake were not significantly different.¹⁰ It is possible that HCV could induce glucose intolerance indirectly by causing cirrhosis or advanced fibrosis by several mechanisms, including decreased glucose uptake as a result of splanchnic shunting and increased gluconeogenesis.10 This is a logical conclusion, given the observation that other forms of liver disease associated with cirrhosis lead to DM.¹¹ In some surveys, NODAT was more frequent in anti-HCV-positive than negative recipients, but no statistical relation between HCV and posttransplant DM was obtained.^12,13 This could be related to the type of immunosuppressive therapy and other factors, such as the limited number of anti-HCV-positive renal transplant recipients, low occurrence of NODAT, short posttransplant follow-up, and successful antiviral therapy before renal trans-plant.^14,15 Therefore, monitoring and prevention of diabetes, coupled with treatment of HCV-infected patients with combination antiviral therapy, should be essential targets after transplant.¹⁶

In this study, we found a relation between NODAT and total dose of steroids. We reported that HCV-positive patients who developed NODAT received a total dose of 3.9 ± 2.1 g in the 3 months posttransplant and patients who did not develop NODAT received 3.3 ± 1.6 g (P = .04; Table 4), and this confirmed by multivariate analysis (Table 8). Our results agree with previously reported results.^17,18 The cause of corticosteroid-related NODAT was assumed to be the stimulation of gluconeogenesis and impairment of glucose uptake by muscles and adipose tissues, which would lead to insulin resistance. During the cyclosporine era, the incidence of NODAT decreased to 3% to 20%.19 Our study was in disagreement with several studies that did not find any effect of cumulative corticosteroid doses on the appearance of NODAT, and that reported that the only risk factor retained for persistent impaired fasting glucose or DM beyond the first year was a higher number of trough levels of tacrolimus > 15 ng/mL during the first month after transplant.^20-23 These studies did not exclude positive family history of diabetes as a risk factor and used deceased donors.

The observed significant association between HCV infection and NODAT has been linked to the use of calcineurin inhibitors, and several investigators suggested an association between HCV and tacrolimus-induced DM after renal transplant.^10,24,25 Although these studies provided strong evidence of an association between tacrolimus-induced NODAT and HCV, they did not give any evidence for the possible underlying mechanism. This relation was not noted in our study and some older reports.^13,26  This may be explained by the small number of patients on tacrolimus without steroids and the short posttransplant duration of recipients on steroid-free immunosuppression because we used a different immunosuppressive protocol.

Our multivariate analysis confirmed the signifi-cant role of sirolimus in the association between HCV and NODAT. Conversion to sirolimus from tacrolimus or cyclosporine has been associated with a significant worsening, rather than improvement, in insulin resistance.²⁷ Sirolimus appears to be diabetogenic.²⁸ This study is in agreement with a prospective study on 26 kidney transplant recipients who were converted from cyclosporine to sirolimus and 15 recipients who were treated with tacrolimus plus sirolimus and discontinued tacrolimus; the switch to sirolimus was associated with 30% increased incidence of impaired glucose tolerance and the development of 4 cases of NODAT as a result of a defect in the compensatory cell response and a decrease in insulin sensitivity.²⁹ In contrast, lower rates of NODAT have been documented in efficacy studies of combination therapy with alternative medications such as mycophenolate mofetil and sirolimus.^30-31 These findings could be explained by the relatively larger doses of corticosteroids, high levels of calcineurin inhibitors in the early posttransplant period, different races, and different lifestyles of the studied patients.

In our study, we detected an important effect of adjuvant therapy on the rate of development of NODAT, especially when basiliximab was used as an induction agent (P < .001). These results are in accordance with a previous report in renal transplant patients who received basiliximab plus prednisone, cyclosporine, and mycophenolate; NODAT, glucose intolerance, and impaired fasting glucose were observed at rates significantly higher than observed in patients receiving prednisone, cyclosporine, and mycophenolate without basiliximab.³² This could be explained because basiliximab is an antibody directed against the interleukin 2 (IL-2) receptor (CD25) and suppresses CD25+CD4+ T lymphocytes. T lymphocytes are thought to be involved in the complex immunology causing type 2 DM.^33,34 Additionally, administration of IL-2 agonists has prevented DM in experimental studies.³⁵

Several risk factors for NODAT were described, and age was the most important factor. A 2-fold increased risk in patients older than 45 years and 3-fold risk in patients older than 63 years at transplant were reported.36 We found a statistical significance between the 4 groups regarding recipient age (P < .001) and donor age (P = .0029), and multivariate analyses confirmed the role of age in occurrence of DM after renal transplant, in agreement with previous reports.25,26 This result is in agreement with a previous study of 2078 nondiabetic renal transplant recipients treated with cyclosporine and prednisone, in a single center in the United States, that showed that recipient age > 45 years was associated with a 2-fold increased risk of developing NODAT (P < .0001).37 Data from the United States Renal Data System showed that first kidney transplant recipients aged between 45 and 59 years had a 1.9 relative risk for NODAT (P < .0001), whereas patients who were aged ≥ 60 years had a 2.6 relative risk (P < .0001).38 However, in our study, the mean age for HCV-positive recipients with NODAT was 35 to 50 years (P < .001), and this difference can be attributed to our selection of younger patients who are expected to resume professional activities after transplant.

In this work, we observed that the increased HLA mismatches and DR mismatches were associated with an increased risk of NODAT. There was a higher percentage of HLA (2 match) (P < .001) and DR
(1 match) (P = .04) in the 4 groups with high statistical significance, similar to results reported by other investigators.^16,19,38 A few studies have not found a correlation between the degree of HLA mismatch and risk of NODAT.³⁹ These findings could be explained by different races and use of deceased donors.

In our study, there was a statistical significance regarding serum creatinine and creatinine clearance at last follow-up (P < .001). The 10-year graft survival was higher in patients who were HCV-negative with NODAT (group 2) (Figure 2), with statistical significance between the 4 groups (P = .012), and this was similar to a previous study that found no difference regarding graft survival⁶ but unlike several studies that reported that NODAT had been associated with worse graft outcomes.^40,41 This difference can be attributed to the fact that graft function was measured only by serum creatinine level.

Some of the limitations of this study were that the HCV diagnosis was based on the serum HCV antibody, and not serum HCV RNA polymerase chain reaction, and only 13 patients had successful pretransplant antiviral therapy. We feel that this reflects typical clinical practice.

In summary, NODAT is a common complication in renal allograft recipients. In our study there was a positive correlation between the development of NODAT and pretransplant HCV-positive status because the percentage of NODAT development was significantly greater in the HCV-positive group (27%) than HCV-negative group (14.5%).

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