Organ transplantation is currently the most effective treatment for end-stage organ failure. Post transplantation diabetes mellitus (PTDM) is a severe complication after organ transplantation that seriously affects the short-term and long-term survival of recipients. However, PTDM is often overlooked or poorly managed in its early stage. This article provides an overview of the incidence, and pathogenesis of and risk factors for PTDM, aiming to gain a deeper understanding of PTDM and improve the quality of life of recipients.

Though posttransplant diabetes mellitus (PTDM, occurring > 45 days after transplantation) and its complications are well described, early post-renal transplant hyperglycemia (EPTH) (< 45 days) similarly puts kidney transplant recipients at risk of infections, rehospitalizations, and graft failure and is not emphasized much in the literature. Proactive screening and management of EPTH is required given these consequences.

The aim of this article is to promote recognition of early post-renal transplant hyperglycemia, and to summarize available information on its pathophysiology, adverse effects, and management.

A PubMed search was conducted for "early post-renal transplant hyperglycemia," "immediate posttransplant hyperglycemia," "post-renal transplant diabetes," "renal transplant," "diabetes," and combinations of these terms. EPTH is associated with significant complications including acute graft failure, rehospitalizations, cardiovascular events, PTDM, and infections.

Patients with diabetes experience better glycemic control in end-stage renal disease (ESRD), with resurgence of hyperglycemia after kidney transplant. Patients with and without known diabetes are at risk of EPTH. Risk factors include elevated pretransplant fasting glucose, diabetes, glucocorticoids, chronic infections, and posttransplant infections. We find that EPTH increases risk of re-hospitalizations from infections (cytomegalovirus, possibly COVID-19), acute graft rejections, cardiovascular events, and PTDM. It is essential, therefore, to provide diabetes education to patients before discharge. Insulin remains the standard of care while inpatient. Close follow-up after discharge is recommended for insulin adjustment. Some agents like dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 receptor agonists have shown promise. The tenuous kidney function in the early posttransplant period and lack of data limit the use of sodium-glucose cotransporter 2 inhibitors. There is a need for studies assessing noninsulin agents for EPTH to decrease risk of hypoglycemia associated with insulin and long-term complications of EPTH.

Hyperglycemia after kidney transplantation is common in both diabetic and non-diabetic patients. Both pretransplant and post-transplant diabetes mellitus are associated with increased kidney allograft failure and mortality. Glucose management may be challenging for kidney transplant recipients. The pathophysiology and pattern of hyperglycemia in patients following kidney transplantation is different from those with type 2 diabetes mellitus. In patients with pre-existing and post-transplant diabetes mellitus, there is limited data on the management of hyperglycemia after kidney transplantation. The following article discusses the nomenclature and diagnosis of pre- and post-transplant diabetes mellitus, the impact of transplant-related hyperglycemia on patient and kidney allograft outcomes, risk factors and potential pathogenic mechanisms of hyperglycemia after kidney transplantation, glucose management before and after transplantation, and modalities for prevention of post-transplant diabetes mellitus.

Recently the role of metabolic signaling pathways has emerged as playing a critical role in dictating the outcome of T cell responses. The uptake and metabolism of the amino acid glutamine is essential for effector T cell activation. Since the growth and expansion of tumor cells relies on similar anabolic and metabolic requirements, we hypothesized that glutamine blockage might represent a promising strategy to promote allograft survival while inhibit tumor growth. 6-Diazo-5-oxo-L-norleucine (DON) was used as a glutamine antagonist. First, an in vitro study of T cell proliferation was performed to examine the ability of glutamine antagonism to inhibit T cell proliferation. Then we investigated whether DON could prolong allograft survival and inhibit tumor growth by using a fully MHC-mismatched mice full thickness skin transplantation model and a mice TC-1 tumor-bearing model. The proliferation study demonstrated that DON inhibited effector T cells proliferation in a dose-dependent manner. We found a marked prolonged graft median survival time and significant tumor inhibition for mice that received DON compared to those that received no treatment. These results highlight that targeting glutamine metabolism can promote allograft acceptance in a long tumor-free period.

From the dawn of civilization, humanity has dreamed of immortality. So why didn't the discovery of the anti-aging properties of mTOR inhibitors change the world forever? I will discuss several reasons, including fear of the actual and fictional side effects of rapamycin, everolimus and other clinically-approved drugs, arguing that no real side effects preclude their use as anti-aging drugs today. Furthermore, the alternative to the reversible (and avoidable) side effects of rapamycin/everolimus are the irreversible (and inevitable) effects of aging: cancer, stroke, infarction, blindness and premature death. I will also discuss why it is more dangerous not to use anti-aging drugs than to use them and how rapamycin-based drug combinations have already been implemented for potential life extension in humans. If you read this article from the very beginning to its end, you may realize that the time is now.

Rapamycin (Sirolimus) slows aging, extends life span, and prevents age-related diseases, including diabetic complications such as retinopathy. Puzzlingly, rapamycin can induce insulin sensitivity, but may also induce insulin resistance or glucose intolerance without insulin resistance. This mirrors the effect of fasting and very low calorie diets, which improve insulin sensitivity and reverse type 2 diabetes, but also can cause a form of glucose intolerance known as benevolent pseudo-diabetes. There is no indication that starvation (benevolent) pseudo-diabetes is detrimental. By contrast, it is associated with better health and life extension. In transplant patients, a weak association between rapamycin/everolimus use and hyperglycemia is mostly due to a drug interaction with calcineurin inhibitors. When it occurs in cancer patients, the hyperglycemia is mild and reversible. No hyperglycemic effects of rapamycin/everolimus have been detected in healthy people. For antiaging purposes, rapamycin/everolimus can be administrated intermittently (e.g., once a week) in combination with intermittent carbohydrate restriction, physical exercise, and metformin.

Diabetes is a common feature in cirrhotic individuals both before and after liver transplantation and negatively affects prognosis. Certain aetiological agents of chronic liver disease and loss of liver function per se favour the occurrence of pre-transplant diabetes in susceptible individuals, whereas immunosuppressant treatment, changes in lifestyle habits, and donor- and procedure-related factors contribute to diabetes development/persistence after transplantation. Challenges in the management of pre-transplant diabetes include the profound nutritional alterations characterizing cirrhotic individuals and the limitations to the use of drugs with liver metabolism. Special issues in the management of post-transplant diabetes include the diabetogenic potential of immunosuppressant drugs and the increased cardiovascular risk characterizing solid organ transplant survivors. Overall, the pharmacological management of cirrhotic patients undergoing liver transplantation is complicated by the lack of specific guidelines reflecting the paucity of data on the impact of glycaemic control and the safety and efficacy of anti-hyperglycaemic agents in these individuals.

AEs during immunosuppressive treatment with tacrolimus are very common. We retrospectively evaluated FK safety and efficacy in a large pediatric liver transplant cohort in Latin America. During 2-year follow-up, we analyzed data from patients who underwent liver transplantation over the period 2010-2012 and recorded FK exposure, AEs, and AR episodes. AEs were classified according causality and severity. Tacrolimus exposure before and during AE was compared using Wilcoxon matched-pairs test. Kaplan-Meier curves were used for survival analysis. In total, 46 patients (out of 72 patients) experienced 69 AEs, such as hypomagnesemia (49%), PTLD (6%), hypertension (6%), and/or nephrotoxicity (22%). 43% of AEs were classified as moderate or serious, and 89% were assigned as probable or definitive. Patients who had one or more AR episodes accounted for 65%. The 12-month acute rejection-free survival was 41% (95% CI, 30.1%-53.1%). A significant difference was observed in FK trough concentrations before and during hypomagnesemia and nephrotoxicity (P<.05). This study is the first report of FK safety in a large group of pediatric liver transplant patients in Latin America. Children experience AEs, even in protocols with low FK doses. Therapeutic monitoring is an important tool to manage immunosuppressive schemes containing tacrolimus in vulnerable populations.

Post-transplantation diabetes mellitus is defined as diabetes that is diagnosed in grafted patients. It affects 20 to 30 % of kidney transplant recipients, with a high incidence in the first year. The increasing age at transplantation and the rising incidence of obesity may increase its prevalence in the next years. Post-transplantation diabetes mellitus is associated with poor outcomes, such as mortality, cardiovascular events or graft dysfunction. Its occurrence is mainly related to immunosuppressive agents, affecting both insulin secretion and sensibility. Immunosuppressants may be iatrogenic, and as such, induce an early and transient diabetes. They may also precociously determine a permanent diabetes, acting here as a promoting factor in patients proned to the development of type 2 diabetes. Lastly, they may behave, far from transplantation, as an additional risk factor for type 2 diabetes. The screening, management and prognosis of these different subtypes of post-transplantation diabetes mellitus will be different.

Kidney transplant is the treatment of choice for end-stage renal disease, but it is not without complications. We review the medical cause of significant renal impairment and complications that developed after kidney transplant in pediatric patients who required hospital admission and intervention and/or who were followed between 2007 and 2016.

A retrospective noninterventional chart review study was conducted in pediatric patients who received a kidney transplant and/or followed at the nephrology clinic at Queen Rania Abdulla Children's Hospital between 2007 and 2016.

In this study, 101 pediatric patients received a total of 103 transplants. Forty-eight patients (47%) experienced deterioration of kidney function out of a total of 53 episodes of complications; 37 of these episodes occurred early (0-6 mo after transplant), and 26 episodes occurred late. The causes of kidney function deterioration were surgical complications, acute tubular necrosis, cell- or antibody-mediated rejection, diabetes mellitus, urinary leak, recurrence of original disease, and chronic allograft nephropathy. Thirteen patients experienced graft loss; 50% of these losses were secondary to noncompliance to immunosuppressant medication treatment after transplant. A total of six patients died; 2 (23%) of these deaths occurred in the first week after transplant, whereas the other 4 patients died over a period of 10 years.

Pediatric kidney transplant is not without complications; however, most of these complications are treatable and reversible. The most serious complications leading to graft loss and death occur early, in the first week after transplant. Improving immunosuppressant compliance after transplant would prevent 50% of graft losses.

Studies have shown that erythropoietin-stimulating agents (ESAs) protect mice against the development of diabetes through direct effects on pancreatic ß cells. However, the effect of ESAs on the incidence of diabetes in humans has not been well studied. It is unknown whether exposure to ESAs is associated with a reduced incidence of new-onset diabetes after transplant (NODAT).

The objective of this study is to examine the relationship between ESA exposure post-renal transplant and the development of NODAT.

We performed a single center, retrospective cohort analysis.

We compared patients who received a first live or deceased donor renal allograft, with any exposure to an ESA vs. those without such exposure and who developed NODAT and who did not. Patients with a prior history of diabetes mellitus or multi-organ transplant, including a second renal transplant were excluded.

NODAT was defined based on the 2008 Canadian Diabetes Association criteria. Multivariate logistic regression analysis was performed to determine factors independently associated with NODAT.

One hundred thirty-two (29 %) patients were exposed to an ESA, four of which developed NODAT compared to 128 who did not develop NODAT (p < 0.0001). Of those not exposed to an ESA, 15 % (48/319) developed NODAT. By Fisher's exact test, exposure to an ESA at any time post-transplant reduced the risk of developing NODAT; odds ratio (OR) = 0.08, 95 % confidence interval (CI) (0.018-0.352), p = 0.0008. Older age; OR = 1.41, 95 % CI (1.036-1.933), p < 0.02, higher random blood sugar at discharge; OR = 1.30, 95 % CI (1.077-1.57), p < 0.006 and deceased donor; OR 2.18 CI (1.009-4.729), p = 0.04 were associated with an increased risk of NODAT.

The limitations of this study include its retrospective nature, single center, and homogenous population; thus, generalizability of the results must be approached with caution.

ESA exposure may be associated with a reduced incidence of NODAT in the post-renal transplant population. The role of ESA in preventing NODAT requires further investigation.

Post-transplant diabetes mellitus (PTDM) is a frequent consequence of solid organ transplantation. PTDM has been associated with greater mortality and increased infections in different transplant groups using different diagnostic criteria. An international consensus panel recommended a consistent set of guidelines in 2003 based on American Diabetes Association glucose criteria but did not exclude the immediate post-transplant hospitalization when many patients receive large doses of corticosteroids. Greater glucose monitoring during all hospitalizations has revealed significant glucose intolerance in the majority of recipients immediately after transplant. As a result, the international consensus panel reviewed its earlier guidelines and recommended delaying screening and diagnosis of PTDM until the recipient is on stable doses of immunosuppression after discharge from initial transplant hospitalization. The group cautioned that whereas hemoglobin A1C has been adopted as a diagnostic criterion by many, it is not reliable as the sole diabetes screening method during the first year after transplant. Risk factors for PTDM include many of the immunosuppressant medications themselves as well as those for type 2 diabetes. The provider managing diabetes and associated dyslipidemia and hypertension after transplant must be careful of the greater risk for drug-drug interactions and infections with immunosuppressant medications. Treatment goals and therapies must consider the greater risk for fluctuating and reduced kidney function, which can cause hypoglycemia. Research is actively focused on strategies to prevent PTDM, but until strategies are found, it is imperative that immunosuppression regimens are chosen based on their evidence to prolong graft survival, not to avoid PTDM.

Upon antigen recognition and co-stimulation, T lymphocytes upregulate the metabolic machinery necessary to proliferate and sustain effector function. This metabolic reprogramming in T cells regulates T cell activation and differentiation but is not just a consequence of antigen recognition. Although such metabolic reprogramming promotes the differentiation and function of T effector cells, the differentiation of regulatory T cells employs different metabolic reprogramming. Therefore, we hypothesized that inhibition of glycolysis and glutamine metabolism might prevent graft rejection by inhibiting effector generation and function and promoting regulatory T cell generation. We devised an anti-rejection regimen involving the glycolytic inhibitor 2-deoxyglucose (2-DG), the anti-type II diabetes drug metformin, and the inhibitor of glutamine metabolism 6-diazo-5-oxo-L-norleucine (DON). Using this triple-drug regimen, we were able to prevent or delay graft rejection in fully mismatched skin and heart allograft transplantation models.

Post-transplantation diabetes mellitus (PTDM) is an important complication related to kidney transplantation (KT), and its occurrence is associated with increased morbidity and mortality. Nevertheless, KT is considered to be the most effective treatment option that offers better quality of life for patients with end-stage kidney disease. This study aimed to describe the occurrence of PTDM and the risk factors associated with its development in kidney transplant patients of a transplantation reference center in the State of Ceará (Brazil). This historical cohort study, based on medical records data, included adult patients undergoing KT from January 2006 to December 2010 in a public tertiary hospital. Multivariate analysis was performed with the use of a logistic regression model, with PTDM presence as dependent variable and the possible risk factors under study as independent variables. Throughout the evaluated period, 430 KTs were performed; 92 patients were excluded. Diabetes mellitus was already present in 9.2% of patients before KT. Hyperglycemia during the 1st month after transplantation occurred in 34.5% of recipients, and the occurrence of PTDM to the end of study was 19.9%. Factors associated with PTDM development were: fasting plasma glucose 1 month after KT (P < .001; odds ratio [OR] 1.05), deceased-donor KT (P = .015; OR 3.53), impaired fasting glucose before transplantation (P = .014; OR 4.10), and acute rejection occurrence (P = .003; OR 6.43). High PTDM occurrence was found, in accordance with the literature. Identification of factors associated with PTDM development, as well as its early diagnosis, could result in long-term improvement in patient and graft survivals.

New-onset diabetes after transplantation (NODAT) is major complication following renal transplantation. It commonly develops within 3-6 mo post-transplantation. The development of NODAT is associated with significant increase in risk of major cardiovascular events and cardiovascular death. Other dysglycemic states, such as impaired glucose tolerance are also associated with increasing risk of cardiovascular events. The pathogenesis of these dysglycemic states is complex. Older recipient age is a consistent major risk factor and the impact of calcineurin inhibitors and glucocorticoids has been well described. Glucocorticoids likely cause insulin resistance and calcineurin inhibitors likely cause β-cell toxicity. The impact of transplantation in incretin hormones remains to be clarified. The oral glucose tolerance test remains the best diagnostic test but other tests may be validated as screening tests. Possibly, NODAT can be prevented by administering insulin early in patients identified as high risk for NODAT. Once NODAT has been diagnosed altering immunosuppression may be acceptable, but creates the difficulty of balancing immunological with metabolic risk. With regard to hypoglycemic use, metformin may be the best option. Further research is needed to better understand the pathogenesis, identify high risk patients and to improve management options given the significant increased risk of major cardiovascular events and death.

Owing to advances in transplant science, increasing numbers of patients are receiving solid organ transplantation. New onset diabetes after transplantation (NODAT) frequently develops in transplant patients and requires acute and often ongoing management of hyperglycemia. The metabolic derangements of NODAT are similar to those of classic type 2 diabetes, and treatment has typically followed diabetes standards of care. Best practices for NODAT management remain to be developed.

The mechanistic suitability of incretins to treat NODAT pathogenesis has been hitherto underappreciated. This review details the specific mechanistic value of incretins in patients with immunosuppression-associated hyperglycemia.

Corticosteroids have long been known to exert their effects on glucose metabolism by decreasing glucose utilization and enhancing hepatic gluconeogenesis. Corticosteroids also significantly and directly reduce insulin secretion, as do calcineurin inhibitors (CNIs), another commonly used group of immunosuppressive drugs that cause hyperglycemia and NODAT. The ability of incretins to counteract immunosuppressant-induced disruptions in insulin secretion suggest that the insulinotropic, glucagonostatic, and glucose-lowering actions of incretins are well suited to treat immunosuppressant-induced hyperglycemia in NODAT. Additional benefits of incretins include decreased glucagon levels and improved insulin resistance. In the case of glucagon-like peptide-1 (GLP-1) receptor agonists, weight loss is another benefit, countering the weight gain that is a common consequence of both hyperglycemia and transplantation. These benefits make incretins very attractive and deserving of more investigation.

Among diabetes treatment options, incretin therapies uniquely counteract immunosuppressant drugs' interference with insulin secretion. We propose an incretin-based treatment paradigm for NODAT management.

The development of new-onset diabetes after kidney transplantation (NODAT) is associated with reduced graft function, increased cardiovascular morbidity and lower patient survival among adult recipients. In the pediatric population, however, the few studies examining NODAT have yielded inconsistent results. Therefore, the true incidence of NODAT in the pediatric population has been difficult to establish. The identification of children and adolescents at risk for NODAT requires appropriate screening questions and tests pre- and post-kidney transplant. Several risk factors have been implicated in the pathogenesis of NODAT and post-transplant glucose intolerance, including African American race, obesity, family history of diabetes and the type of immunosuppressant regimen. Moreover, uremia per se results in a state of insulin resistance that increases the risk of developing diabetes post-transplant. When an individual becomes glucose intolerant, early lifestyle modification and antihyperglycemic measures with tailoring of the immunosuppressant regimen should be implemented to prevent the development of NODAT. For the child or adolescent with NODAT, antihyperglycemic therapy should be prescribed in order to achieve optimal glycemic control, ultimately reducing complications and improving overall allograft and patient survival. In this article, we review the risk factors, screening methods, diagnosis, management and outcome of children and adolescents with NODAT and post-kidney transplant glucose intolerance.

New-onset diabetes after transplantation (NODAT) is associated with decreased graft survival and an increased risk for cardiovascular disease. The objective of this study was to evaluate the risk factors for development of NODAT and its' relationship with arterial stiffness and left ventricular mass index (LVMI) in kidney transplant recipients.

159 kidney transplant recipients were selected from our transplantation center who underwent renal transplantation between years 2007 and 2010.

Among 159 patients, 57 (32.2%) patients were with NODAT who were significantly older than patients without diabetes (P: 0.0001). Patients with NODAT had significantly higher pulse wave velocity (PWv) (P: 0.033) and left ventricular mass index LVMI (P: 0.001) compared to patients without NODAT. Further analysis was done according to LVMI as follows: LVMI > 130 g/m(2) (n: 57) and LVMI ≤ 130 g/m(2) (n: 102). We observed higher office systolic and diastolic BP, serum trygliceride, glucose, creatinine, age, and HbA1c (P: 0.0001) levels in patients with LVMI > 130 g/m(2). Linear regression analysis revealed that HbA1c was the major determinant of LVMI (P: 0.026, β: 0.361).

HbA1c is the major determinant of LVMI, so strict control of serum glucose levels is essential for preventing cardiovascular disease in patients with NODAT.

Renal transplant offers a definitive therapeutic modality for patients with end-stage renal disease; however, 50% to 70% of these patients have graft dysfunction after the transplant. Proactive prevention management of metabolic complications may reduce posttransplant morbidity and mortality in these patients.

A retrospective and prospective review of 120 kidney transplant recipients during 5 years' follow-up was performed to analyze the incidence and status of the various metabolic complications after a renal transplant.

In our study, postrenal transplant diabetes mellitus was seen in 9 of 120 patients (7.5%). The incidence of posttransplant diabetes mellitus was 5% in tacrolimus-treated patients (n=6) compared with 2.5% in cyclosporine-treated patients (n=3). Dyslipidemia, as hypercholesterolemia and hyper-triglyceridemia, was seen in 31 recipients (25.83%). Significant posttransplant hyperlipidemia was documented (P < .05). Further, it was noted that 25 patients who developed hyperlipidemia (20.83%) were taking cyclosporine-based therapy, while 6 were treated with tacrolimus-based therapy (5%; P < .05). However, most subjects with hyperlipidemia had renal graft dysfunction. Posttransplant erythrocytosis affected 9 renal transplant recipients (7.5%) with a mean (±SD) hematocrit of 41.3%±6.7%. A statistically significant correlation was seen between prerenal and postrenal transplant hematocrit by 12 months. Hyperparathyroidism was observed in 1 renal transplant patient (1.25%).

On the basis of this study, we conclude that posttransplant diabetes mellitus occurred in 7.5% patients, hypercholesteremia and hyper-triglyceridemia occurred in 25.83% patients, posttransplant erythrocytosis affected 7.5% patients, and hyperparathyroidism occurred in 1 renal transplant patient (1.25%). Moreover, dyslipidemia, contributed to progressive graft dysfunction.

New onset of diabetes after transplantation (NODAT) is a known complication of renal transplantation, but early glycaemic status after transplantation has not been described prospectively. This study aimed to assess blood glucose (BG) levels immediately following kidney transplantation in non-diabetic subjects and to explore their relationship to later graft outcomes and NODAT occurrence.

Over a 9-month period, 43 consecutive non-diabetic patients who received a kidney transplant were prospectively investigated. During the first 4 days after transplantation, fasting BG was measured and the 24-h BG profile assessed by continuous glucose monitoring (CGM). Capillary BG was measured on hospital admittance and at least four times a day for CGM calibration thereafter. All adverse events were recorded, and fasting BG and HbA1c were assessed at 3, 6 and 12 months and at the last visit to our centre.

Immediately following renal transplantation, capillary BG was 12.2 ± 3.8 mmol/L. On day 1 (D1), fasting BG was 9.9 ± 4.3 mmol/L and decreased to 6.0 ± 1.5 mmol/L on D3. The CGM-reported mean 24-h BG (mmol/L) was 10.2±2.4 on D1, 7.7 ± 1.3 on D2 and 7.5 ± 1.1 on D3. From D1 to D4, 43% of patients spent>12h/day with BG levels>7.7 mmol/L. While morbidity during the 3 months following transplantation appeared unrelated to BG, the first post-transplantation capillary BG measurement and fasting BG on D1 tended to be higher in patients who developed diabetes 3 months later. Tacrolimus treatment was associated with a higher incidence of dysglycaemia at 3 and 6 months. After a mean follow-up of 72 months, NODAT was frequently seen (18.6%), and was associated with tacrolimus medication (P<0.01) and a higher rate of renal transplantation failure (RR: 3.6, P<0.02).

Hyperglycaemia appears to be a nearly constant characteristic immediately following transplantation in non-diabetic kidney recipients. Higher BG values could identify patients at risk for later post-transplant diabetes and graft failure.

Chronic renal failure is an important and common complication of diabetes mellitus; hence, renal transplantation is a frequent and the acceptable treatment in patients with diabetic nephropathy requiring renal replacement therapy. On the other hand, renal transplantation and its conventional treatment can lead to increased diabetes outbreak in normoglycemic recipients. Also, uncontrolled hyperglycemia may be increased and allograft lost thus decreasing patient survival.

We aimed to assess the frequency of hyperglycemia in transplant patients and its risk factors.

A large retrospective study was performed on 3342 adult kidney transplant recipients between 2008 and 2010. Demographic and laboratory data were gathered for each patient. All tests were done in a single laboratory and hyperglycemia was defined as a fasting plasma glucose of > 125 mg/dL. Univariate and multivariate logistic regression analyses were used to determine the risk factors of hyperglycemia following kidney transplantation.

There were 2120 (63.4%) males and 1212 (36.3%) females. Prevalence of hyperglycemia was 22.5%. By univariate linear regression, hyperglycemia was significantly higher in patients with CMV infection (P = 0.001), elevated serum creatinine (P = 0.000), low HDL (P = 0.01), and increased blood levels of cyclosporine (P = 0.000). After adjusting for covariates by multivariate logistic regression, the hyperglycemia rate was significantly higher for patients with Cyclosporine trough level > 250 (P = 0.000), serum creatinine > 1.5 (P = 0.000) and HDL < 45 (P = 0.03).

This study indicated that hyperglycemia is a common metabolic disorder in Iranian kidney transplant patients. Risk factors for hyperglycemia were higher Cyclosporine level, impaired renal function, and reduced HDL value.

Immunosuppressants are an important cause of posttransplantation diabetes mellitus. We have shown that tacrolimus and sirolimus induce hyperglycemia and hyperinsulinemia in normal rats. We hypothesized that metformin, given concurrently with tacrolimus and/or sirolimus, prevents disturbances in glucose and insulin metabolism.

Eight groups (n=6) of normal Sprague-Dawley rats were studied: four groups received tacrolimus, sirolimus, tacrolimus/sirolimus, or control for 14 days, and four more groups received similar treatments along with metformin. Daily glucoses were measured. All rats were administered an oral glucose challenge before sacrifice. Pancreata were analyzed by terminal deoxynucleotide tranferase-mediated dUTP nick-end labeling staining and immunohistochemistry.

Tacrolimus, sirolimus, and tacrolimus/sirolimus impaired glucose tolerance compared to control. Sirolimus and tacrolimus/sirolimus also increased random blood glucose levels. Sirolimus alone resulted in hyperinsulinemia after oral glucose challenge compared to control. In the sirolimus/metformin and tacrolimus/sirolimus/metformin groups, mean daily random glucose was no longer increased, although the response to glucose challenge was still impaired. Metformin decreased pancreatic exocrine and trended to decrease endocrine apoptosis in tacrolimus/sirolimus group and reduced islet insulin content in sirolimus group.

This is the first study to show that metformin can improve immunosuppressant-induced hyperglycemia, when administered concurrently, and reduces exocrine apoptosis (reducing the impact on potential islet progenitor cells).

New-onset diabetes after transplantation (NODAT) is associated with increased risk of allograft failure, cardiovascular disease and mortality, and therefore, jeopardizes the success of renal transplantation. Increased awareness of NODAT and the prediabetic states (impaired fasting glucose and impaired glucose tolerance, IGT) has fostered previous and present recommendations, based on the management of type 2 diabetes mellitus (T2DM). Unfortunately, the idea that NODAT merely resembles T2DM is potentially misleading, because the opportunity to initiate adequate anti-hyperglycaemic treatment early after transplantation might be given away for 'tailored' immunosuppression in patients who have developed NODAT or carry personal risk factors. Risk factor-independent mechanisms, however, seem to render postoperative hyperglycaemia with subsequent development of overt or 'full-blown' NODAT, the unavoidable consequence of the transplant and immunosuppressive process itself, at least in many cases. A proof of the concept that timely preventive intervention with exogenous insulin against post-transplant hyperglycaemia may decrease NODAT was recently provided by a small clinical trial, which is awaiting confirmation from a multicentre study. However, because early insulin therapy aimed at beta-cell protection seems to contrast the currently recommended, stepwise approach of 'watchful waiting' prior to pancreatic decompensation, we here aim at reviewing recent concepts regarding the development, prevention and treatment of NODAT, some of which seem to challenge the traditional view on T2DM and NODAT. In summary, we suggest a novel, risk factor-independent management approach to NODAT, which includes glycaemic monitoring and anti-hyperglycaemic treatment in virtually everybody after transplantation. This approach has widespread implications for future research and is intended to tackle NODAT and also ultimately cardiovascular disease.

Postrenal transplantation diabetes mellitus (PTDM), or new-onset diabetes after organ transplantation, is an important chronic transplant-associated complication. Similar to type 2 diabetes, decreased insulin secretion and increased insulin resistance are important to the pathophysiologic mechanism behind the development of PTDM. However, β-cell dysfunction rather than insulin resistance seems to be a greater contributing factor in the development of PTDM. Increased age, family history of diabetes, ethnicity, genetic variation, obesity, and hepatitis C are partially accountable for an increased underlying risk of PTDM in renal allograft recipients. In addition, the use of and kinds of immunosuppressive agents are key transplant-associated risk factors. Recently, a number of genetic variants or polymorphisms susceptible to immunosuppressants have been reported to be associated with calcineurin inhibition-induced β-cell dysfunction. The identification of high risk factors of PTDM would help prevent PTDM and improve long-term patient outcomes by allowing for personalized immunosuppressant regimens and by managing cardiovascular risk factors.

This retrospective analysis evaluated the impacts of sirolimus (SRL), cyclosporine (CsA), and steroids (S) on the occurrence, treatment, and complications of new-onset diabetes after transplantation (NODAT).

We compared 4 groups: group 1, SRL plus full-exposure CsA/S (n = 118); group 2, full-exposure CsA/S/no SRL ± antiproliferative drug (n = 141); group 3, SRL plus reduced CsA exposure/S (n = 212); and group 4, no SRL/full-exposure CsA/S ± antiproliferative drug (n = 43).

NODAT rates reflected the level of CsA exposure; at 10 years 54% versus 30% for groups 1 versus 2 (P = .0001); at 5 years 30% versus 21% for Groups 3 versus 4 (P = .3); 81% of cases were detected within 1 year. The lower NODAT rate in group 3 reflected a benefit of reduced CsA exposure (P = .02; hazard ratio (HR), 1.006). Group 1 showed higher CsA (P = .0001) and lower SRL concentrations (P = .016) versus group 3. CsA exposure closely correlating with NODAT among group 1 (P = .0001) was the major difference between groups 1 and 3 (P = .04; HR, 0.97). Differences in steroid treatment did not play a significant role in NODAT. Comparing groups 1 and 2, SRL was an independent risk factor for NODAT (P = .004; HR, 3.5).

Our 10-year experience revealed SRL to be an etiologic agent for NODAT, displaying interactive, possibly pharmacokinetic, and pharmacodynamic effects with concomitant CsA in combination treatment.

New-onset diabetes after transplantation (NODAT) is a multifactorial, complex metabolic disorder associated with impaired long-term graft function, reduced recipient survival, and increased risks of cardiovascular disease and infectious complications. The impact of NODAT is generally underestimated partly due to the inconsistent criteria that have been previously used for its diagnosis and to the generally short observation periods. The aim of this article was to review the recent literature on NODAT and to highlight the novel implications.

The 2010 American Diabetes Association guidelines provide useful, simplified criteria to unify the diagnosis including application of hemoglobin A1C levels. We sought to establish the impact of various modifiable and nonmodifiable risk factors. A vast number of papers have examined the effects of immunosuppressive medications on the development of NODAT: Neither calcineurin inhibitor nor sirolimus (SRL) or steroids seems to be innocent of contributing to it. Immunosuppressants account for 74% of the occurrence of NODAT. Among modifiable risk factors, obesity is independent and significant, with great prevalence in the population. In additional to lifestyle modifications, the role of bariatric surgery (BS) either before or after transplantation is highlighted herein as a strategy to reduce disease in the view of the results among overweight, nontransplanted patients.

Because of the strong association between high glucose values in the early posttransplant period and the development of NODAT, the condition must be recognized early after (or even before) transplantation by intensive screening. Patients at risk for NODAT must modify appropriate risk factors and particularly undergo pretransplant planning and/or posttransplant adjustment individualizing immunosuppressive therapy to mitigate the risk of this serious complication.

New-onset diabetes after transplantation (NODAT) is a major posttransplant complication associated with lower allograft and recipient survival. Our objective was to determine whether metabolic syndrome pretransplant is independently associated with NODAT development.

We recruited 640 consecutive incident nondiabetic renal transplant recipients from three academic centers between 1999 and 2004. NODAT was defined as the use of hypoglycemic medication, a random plasma glucose level more than 200 mg/dL, or two fasting glucose levels more than or equal to 126 mg/dL beyond 30 days posttransplant.

Metabolic syndrome was common pretransplant (57.2%). NODAT developed in 31.4% of recipients 1 year posttransplant. Participants with metabolic syndrome were more likely to develop NODAT compared with recipients without metabolic syndrome (34.4% vs. 27.4%, P=0.057). Recipients with increasing number of positive metabolic syndrome components were more likely to develop NODAT (metabolic syndrome score prevalence at 1 year: 0 components-0.0%, 1-24.2%, 2-29.3%, 3-31.0%, 4-34.8%, and 5-73.7%, P=0.001). After adjustment for demographics, age by decade (hazard ratio [HR] 1.34 [1.20-1.50], P<0.0001), African American race (HR 1.35 [1.01-1.82], P=0.043), cumulative prednisone dosage (HR 1.18 [1.07-1.30], P=0.001), and metabolic syndrome (HR 1.34 [1.00-1.79], P=0.047) were independent predictors of development of NODAT at 1 year posttransplant. In a multivariable analysis incorporating the individual metabolic syndrome components themselves as covariates, the only pretransplant metabolic syndrome component to remain an independent predictor of NODAT was low high-density lipoprotein (hazard ratio [HR] 1.37 [1.01-1.85], P=0.042).

Metabolic syndrome is an independent predictor for NODAT and is a possible target for intervention to prevent NODAT. Future studies to evaluate whether modification of metabolic syndrome factors pretransplant reduces NODAT development are needed.

Diabetes mellitus is the commonest cause of end-stage renal failure in both Australia and New Zealand. In addition, the burden of diabetes is prominent in those with chronic kidney disease who have not yet reached the requirement for renal replacement therapy. While diabetes is associated with a higher incidence of mortality and morbidity in all populations studied with kidney disease, little is known about optimal treatment strategies for hyperglycaemia and the effects of glycaemic treatment in this large group of patients. Metformin is recommended as the drug of first choice in patients diagnosed with type 2 diabetes in the USA, Europe and Australia. There are potential survival benefits associated with the use of metformin in additional to recent studies suggesting benefits in respect to cardiovascular outcomes and metabolic parameters. The use of metformin has been limited in patients with renal disease because of the perceived risk of lactic acidosis; however, it is likely that use of this drug would be beneficial in many with chronic kidney disease. Thus the potential benefits and harms of metformin are outlined in this review with suggestions for its clinical use in those with kidney disease.

Adiponectin (ADPN) has been reported to be inversely correlated with insulin resistance (IR) in uremic subjects and following kidney transplantation. Kidneys have been suggested to play a part in ADPN clearance. This study sought to evaluate this hypothesis. We enrolled 67 candidates with end-stage renal disease (ESRD) along with 30 healthy unrelated donors. Plasma ADPN, IR (based on the homeostasis model assessment for IR index), and glomerular filtration rates were compared between control and patient groups. The correlations of the aforementioned variables were also compared in the patient group 1 day before and 14 days following transplantation. The changes in measured parameters were also compared with control group values. The glomerular filtration rate was significantly decreased among recipients. ADPN levels were remarkably higher in the patient group before transplantation when compared with healthy subjects (P<.001) and remained significantly higher thereafter (P<.001). Insulin resistance was higher, albeit not significantly, among ESRD patients compared with controls (P>.05) and it increased following transplantation (P=.03). There was no correlation between ADPN, IR, and glomerular filtration rate in normal individuals or ESRD patients before or after transplantation. It is our assumption that mechanisms other than kidney function are probably involved in ADPN metabolism in ESRD patients and in the immediate phase following transplantation. It does not seem that ADPN substantially affects IR either in ESRD or transplantation patients.

Post-transplant diabetes mellitus (PTDM) worsens outcomes after kidney transplantation, and immunosuppression agents contribute to PTDM. We have previously shown that tacrolimus (TAC) and sirolimus (SIR) cause hyperglycemia in normal rats. While there is little data on the mechanism for immunosuppressant-induced hyperglycemia, we hypothesized that the TAC and SIR-induced changes are reversible. To study this possibility, we compared normal rats treated for 2 weeks with either TAC, SIR, or a combination of TAC and SIR prior to evaluating their response to glucose challenge, with parallel groups also treated for 2 weeks after which treatment was stopped for 4 weeks, prior to studying their response to glucose challenge. Mean daily glucose and growth velocity was decreased in SIR, and TAC+SIR-treated animals compared to controls (P < 0.05). TAC, SIR, and TAC+SIR treatment also resulted in increased glucose response to glucose challenge, compared to controls (P < 0.05). SIR-treated animals also had elevated insulin concentrations in response to glucose challenge, compared to controls (P < 0.05). Insulin content was decreased in TAC and TAC+SIR, and islet apoptosis was also increased after TAC+SIR treatment (P < 0.05). Four weeks after treatments were stopped, all differences resolved between groups. In conclusion, TAC, SIR, and the combination of TAC+SIR-induced changes in glucose and insulin responses to glucose challenge that were accompanied by changes in islet apoptosis and insulin content. These changes were no longer present 4 weeks after cessation of therapy suggesting immunosuppressant-induced changes in glucose metabolism are likely reversible.

Hypoglycaemia poses a significant management challenge in patients with unresectable functional malignant insulinoma. Novel agents such as mammalian target of rapamycin (mTOR) inhibitors and radiolabelled peptides may be effective where there is failure of conventional therapy.

We present the cases of two men diagnosed with inoperable malignant insulinoma and hepatic metastases who developed severe symptomatic hypoglycaemia, and review potential therapies for glycaemic support.

Despite treatment with diazoxide, frequent oral carbohydrate, prednisolone and somatostatin analogue therapy, both men required hospital admission for treatment with continuous i.v. dextrose. Both were treated with Lutetium-177 octreotate. One man was also treated with everolimus, a mTOR inhibitor.

Use of Lutetium-177 octreotate, and in one case everolimus, successfully achieved normoglycaemia, facilitating safe discharge from hospital. Both men also had regression in the size and number of hepatic metastases.

Lutetium-177 octreotate and everolimus are options for managing hypoglycaemia due to unresectable malignant insulinoma when refractory to conventional supportive therapies.

Posttransplant diabetes mellitus (PTDM) is a common and serious complication of renal transplantation. Estimates of the incidence of PTDM after renal transplantation vary between 2% and 54%. The aim of the present study was to evaluate the incidence and risk factors for PTDM among our renal transplant patients.

In this study we evaluated 121 nondiabetic patients with end-stage renal disease (ESRD) who underwent kidney transplantation for the first time at our centers since 2005. All patients received the same protocol of immunosuppressive therapy. PTDM was defined according to the clinical practice recommendations of the American Diabetes Association.

At 12 months following renal transplantation, 9.9% of patients developed PTDM. Patients with PTDM were significantly older (P = .013) and had higher body mass index (P = .001). There were significant differences (P <or= .05) between PTDM and non-PTDM patients with respect to systolic blood pressure, serum triglycerides (TG), peritoneal dialysis as renal replacement therapy before transplantation, and duration of pretransplant dialysis therapy. Upon multivariate analysis, serum TG, systolic blood pressure, and body mass index were associated with PTDM (P <or= .05).

The incidence at 12 months of PTDM among our renal transplant recipients was 9.9%. The most important factors associated with PTDM were serum TG, systolic blood pressure, and body mass index.

This article reviews the clinical aspects and epidemiological links between diabetes mellitus and renal transplantation, and emphasizes areas that warrant further clarification. In particular, we summarize the data for various immunosuppression medications on the risk of new-onset diabetes after transplantation (NODAT). An increased mechanistic understanding of new-onset diabetes might provide new insights into the pathophysiology of this complication after solid organ transplantation. Claims that selecting immunosuppression regimen to minimize the risk of NODAT, nevertheless, are currently not supported by the scientific published work. Intuitively, strategies that aim to change the underlying biology of the disease process of NODAT are desirable; among them, lifestyle modification is currently the most promising in terms of real benefit with the least risk.

New-onset diabetes mellitus is a common complication of solid organ transplantation and is likely to become even more common with the current epidemic of obesity in some countries. It has become clear that both new-onset diabetes and prediabetic states (impaired fasting glucose and impaired glucose tolerance) negatively influence graft and patient survival after transplantation. This observation forms the basis for recommending meticulous screening for glucose intolerance before and after transplantation. Although a number of clinical factors including age, weight, ethnicity, family history, and infection with hepatitis C are closely associated with the new-onset diabetes mellitus, immunosuppression with corticosteroids, calcineurin inhibitors and possibly sirolimus plays a dominant role in its pathogenesis. Management of new-onset diabetes after transplantation generally conforms to the guidelines for treatment of type 2 diabetes mellitus in the general population. However, further studies are needed to determine the optimal immunosuppressive regimens for patients with this disorder.

The short-term outcomes of kidney transplant recipients have improved dramatically in the past 20 years, in large part resulting from the availability of more potent immunosuppressive drugs capable of preventing or treating acute allograft rejection. Ironically, side effects from these same immunosuppressants play a role in the long-term morbidity and mortality of this patient population. As kidney transplant recipients survive for longer periods of time with functioning allografts, primary care physicians will likely become more involved in their management, mandating at least a basic understanding of immunosuppression and its complications.

As patient survival after solid organ transplantation continues to improve, comorbidites associated with chronic hyperglycemia will assume increasing importance in limiting outcomes and quality of life. New-onset diabetes mellitus commonly occurs in the posttransplant setting and is associated with multiple complications including graft loss, cardiovascular disease, infection, and death. Furthermore, recent studies have begun to highlight the very high posttransplant prevalence and the significant cardiovascular implications of the prediabetic states of impaired fasting glucose and impaired glucose tolerance, indicating that the overall burden of transplantation-associated hyperglycemia is far greater than previously appreciated. Shared and distinct pathogenic factors and clinical repercussions exist among the organ-specific transplant scenarios. Diabetogenic immunosuppressive agents are common to all organ transplant settings, whereas glucose regulation is also strained by the restoration of failed hepatic and renal function. The atherogenic properties of hyperglycemia are particularly significant in the kidney transplant population, which has a marked predisposition to cardiovascular disease, whereas accelerated cardiac allograft vasculopathy and liver fibrosis have been associated with hyperglycemia in the heart and liver transplant settings, respectively. Aggressive screening will effectively detect transplant-associated hyperglycemia, whereas risk factor modification, lifestyle intervention and, where appropriate, drug therapy, may decrease its impact. Topics of future investigation should include the use of emerging diabetes therapies and avenues for the prevention and reversal of transplant-associated hyperglycemia.

We conducted a cross-sectional study to estimate the prevalence of metabolic syndrome, a clustering of risk factors associated with cardiovascular disease, among 86 adults who had allogeneic hematopoietic-cell transplant (HCT) as compared with 258 age- and gender-matched US population controls selected from the 2005-2006 National Health and Nutrition Examination Survey database. The median age at study enrollment was 50 years (range, 21-71), and patients were at a median of 3 years (range, 1-21) from HCT. The prevalence of metabolic syndrome was 49% (95% confidence intervals (CI), 38-60%) among HCT recipients, a 2.2-fold (95% CI, 1.3-3.6, P=0.002) increase compared with controls. The prevalence rates of elevated blood pressure and hypertriglyceridemia were significantly higher among HCT recipients than among controls, but the prevalence rates of abdominal obesity, elevated blood glucose and low high-density lipoprotein cholesterol were not. HCT survivors with metabolic syndrome were more likely to have microalbuminuria (43 vs 10%) and elevated creatinine (31 vs 11%). No patient, donor or transplant characteristics were associated with the diagnosis of metabolic syndrome. We conclude that metabolic syndrome occurs frequently among allogeneic HCT survivors who are seen by transplant physicians. Approaches to screening, prevention and management of metabolic syndrome should be developed for HCT recipients.