DIABETICMedicine DOI: 10.1111/dme.12534
Review Article New-onset diabetes after renal transplantation N. Tufton1, S. Ahmad1, C. Rolfe2, R. Rajkariar2, C. Byrne2 and T. A. Chowdhury1 1 Department of Diabetes and Metabolism, Barts and the London School of Medicine and Dentistry, London, UK and 2Department of Nephrology, Barts and the London School of Medicine and Dentistry, London, UK
Accepted 24 June 2014
Abstract Renal transplantation has important benefits in people with end-stage renal disease, with improvements in mortality, morbidity and quality of life. Whilst significant advances in transplantation techniques and immunosuppressive regimens have led to improvements in short-term outcomes, longer-term outcomes have not improved dramatically. New-onset diabetes after transplantation appears to be a major factor in morbidity and cardiovascular mortality in renal transplant recipients. The diagnosis of new-onset diabetes after renal transplantation has been hampered by a lack of clarity over diagnostic tests in early studies, although the use of the WHO criteria is now generally accepted. HbA1c may be useful diagnostically, but should probably be avoided in the first 3 months after transplantation. The pathogenesis of new-onset diabetes after renal transplantation is likely to be related to standard pathogenic factors in Type 2 diabetes (e.g. insulin resistance, b-cell failure, inflammation and genetic factors) as well as other factors, such as hepatitis C infection, and could be exacerbated by the use of immunosuppression (glucocorticoids and calcineurin inhibitors). Pre-transplant risk scores may help identify those people at risk of new-onset diabetes after renal transplantation. There are no randomized trials of treatment of new-onset diabetes after renal transplantation to determine whether intensive glucose control has an impact on cardiovascular or renal morbidity, therefore, treatment is guided by guidelines used in non-transplant diabetes. Many areas of uncertainty in the pathogenesis, diagnosis and management of new-onset diabetes after renal transplantation require further research. Diabet. Med. 31, 1284–1292 (2014)
Introduction Diabetes mellitus is a pressing public health issue as a result of its increasing prevalence and associated high social and economic costs. In the UK in 2013, ~10% of healthcare spending was directly related to diabetes or its attendant complications [1]. Diabetes complications are multi-system and are placing an increasing burden on cardiovascular, renal, ophthalmological, podiatric and vascular services. Renal disease accounts for ~20% of deaths in people with Type 1 diabetes and 10% of deaths in Type 2 diabetes, and there are currently nearly 7000 people with diabetes on the UK dialysis or transplant programme [2]. Renal transplantation has a proven clinical benefit in people with end-stage renal failure. Whilst diabetes is a common cause of end-stage renal failure, new-onset diabetes after transplantation (NODAT) can be a significant complication of renal transplantation. The condition may have adverse effects on renal and other outcomes after renal transplantation. The Correspondence to: Tahseen A. Chowdhury. E-mail: [email protected]
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present review focuses on the current knowledge of the pathogenesis, risk factors and management of this specific form of diabetes amongst people with renal disease.
Search strategy and selection criteria We searched the Medline database up to 16 December 2013 for the terms ‘diabetes’ and ‘renal transplantation’, or ‘new-onset diabetes after transplantation’ with emphasis on publications from the last 10 years, although seminal older publications were also included. Articles from the reference list of these publications were also considered.
What is new-onset diabetes after transplantation and how common is the condition? Diagnosis
New-onset diabetes after transplantation as a complication of renal transplantation was first described in 1964 [3], and
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has more recently been recognized as having an important impact on cardiovascular and renal morbidity. NODAT refers to the occurrence of diabetes in a person after organ transplantation who was previously not known to have diabetes, and has been reported after transplants of kidney, liver, lung and heart, as well as bone marrow and haemopoietic stem cells. A number of definitions have been suggested since its recognition, including ‘the uninterrupted need for glucose-lowering therapy for at least 3 months after transplantation’, ‘the use of insulin postoperatively’, ‘the need for oral agents’ and ‘fasting glucose values between 7 and 13mmol/l’. International consensus guidelines published in 2003, and updated in 2004 used the WHO and American Diabetes Association guidance on diagnosis of diabetes mellitus and impaired glucose tolerance [4]. These diagnostic criteria incorporate symptoms, fasting glucose measurements and 2-h postprandial readings after an oral glucose tolerance test (Table 1). Individuals with fasting glucose values of 6.1–6.9 mmol/l (110–125mg/dl) are defined as having impaired fasting glucose and those with 2-h glucose values of 7.8–11.1 mmol/l (140–199mg/dl) after an oral glucose tolerance test are defined as having impaired glucose tolerance. Both conditions are associated with an increased risk of developing diabetes and cardiovascular disease. More recently, the WHO has suggested that HbA1c can be used to diagnose diabetes in a general population, with a diagnostic level of ≥ 48 mmol/mol (6.5%) on two occasions in an asymptomatic individual [5]. In renal transplantation, HbA1c should probably not be used < 3 months after transplant, as the test may not be accurate before adequate time is allowed for synthesis and glycation of new haemoglobin in the post-transplant period. One study has suggested that an HbA1c level > 39 mmol/mol (5.7%) at 10 weeks can identify the need for oral glucose tolerance test assessment, with a 91% sensitivity [6]. A further study has suggested that an HbA1c level > 44 mmol/mol (6.2%) at 3 months after transplant (sensitivity 100% and specificity 88.9%) and a level of 47 mmol/mol (6.45%) at 12 months (sensitivity 100% and specificity 87.5%) are useful thresholds, and concluded that HbA1c ≥ 48 mmol/mol (6.5%) could be used
to diagnose NODAT at least 3 months after transplantation [7]. The validity of using HbA1c for routine screening or as a diagnostic tool is yet to be validated because of significant ethnic variation, and its value as a pre-transplant screening tool is also unclear. Some studies suggest that postprandial glucose may be useful diagnostically [7–9], although there is evidence to suggest that increasing levels of fasting glycaemia are associated with increasing risk of cardiovascular events after transplantation [10]. A recent study compared diagnostic criteria at different time points after transplantation [11]. Of the 26 people screened at 6 weeks after transplant, NODAT was detected in 46% using capillary blood glucose, vs 4% using HbA1c, 12% using an oral glucose tolerance test, and 0% using fasting plasma glucose. At 3 months, NODAT was detected in 14% by HbA1c vs 20% with oral glucose tolerance test and 2% with fasting plasma glucose, with the corresponding figures at 12 months being 4, 6 and 2%. This suggests that fasting plasma glucose has significant limitations diagnostically, possibly as a result of calcineurin inhibitors/steroid-based immunosuppression drugs inducing postprandial peaks in glucose rather than fasting hyperglycaemia. The use of an oral glucose tolerance test before transplantation has been evaluated as a screening tool to identify people at high risk of developing NODAT [12]. In a predominantly white population, one such study found 8.1% of a pre-transplant population had undiagnosed diabetes, and 78% of these would have been missed if only fasting blood glucose had been used. The 2004 updated guidelines on the screening and management of NODAT recommend performing an oral glucose tolerance test in those with intermediate fasting glucose (110–125 mg/dl, 6.1–6.9 mmol/l) and HbA1c testing to be included as part of screening after the initial 3-month period has elapsed, as well as taking a full personal and family glucose history and screening for other components of metabolic syndrome in pre-transplantation consultations [4]. It is also notable that post-transplantation hyperglycaemia and diabetes can be a transient phenomenon, so although such individuals may be labelled as having diabetes
Table 1 Diagnostic criteria, according to the WHO, for new-onset diabetes after transplantation
Diabetes Random plasma glucose
Fasting plasma glucose 2-h plasma glucose after 75 g glucose HbA1c (not yet considered diagnostic in the immediate post-transplant period)
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11.1 mmol/l (200 mg/dl)+Symptoms (polyuria, polydipsia, weight loss, tiredness) ≥ 7.0 mmol/l (≥ 126 mg/dl) ≥ 11.1 mmol/l (200 mg/dl) > 6.5% (48 mmol/mol)
Impaired fasting glucose
Impaired glucose tolerance
–
–
6.1–6.9 mmol/l (110–125 mg/dl) – –
– 7.8–11.0 mmol/l (140–199 mg/dl) Pre-diabetes:42–47 mmol/mol (6.0–6.4%)
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using the above criteria, this may subsequently resolve, but they remain at a higher risk of developing diabetes in the future [10]. Conversely, any individual identified with impaired glucose tolerance should be monitored more closely after transplant because of their high risk of developing NODAT [4].
reversible because of the associated immunosuppressive medications (Table 2) [17]. Similarly to Type 2 diabetes, peripheral insulin resistance and impaired insulin secretion have been implicated in the development of NODAT. b-cell dysfunction appears to play an important role [18], as demonstrated by the fact that early aggressive treatment of hyperglycaemia in the early post-transplant period may have a protective effect against NODAT [19]. Insulin resistance tends to increase after transplantation as a result of drug therapy, including steroids and calcineurin inhibitors. Calcineurin inhibitors may affect both insulin sensitivity and insulin secretion by a variety of ill-defined mechanisms (see below). Unsurprisingly, pre-transplant obesity, inflammation and markers of insulin resistance appear to be risk markers for NODAT. Some investigators have shown that low levels of adiponectin (an adipocytokine which enhances insulin sensitivity), high concentrations of C-reactive protein, high triglyceride levels and elevated BMI before transplant predict the development of NODAT [20].
Epidemiology
Undiagnosed diabetes is common among people awaiting renal transplantation. One large study in white people on the waiting list for renal transplantation found that 8% of people had undiagnosed diabetes based on fasting or 2-h blood glucose readings, and 37% had impaired fasting glucose or impaired glucose tolerance [12]. The reported incidence of NODAT, however, varies widely between studies, with anywhere between 2 and 53% of renal transplant recipients developing diabetes in the first year after transplant. The wide range of incidence reported may be attributable to different diagnostic criteria, with many studies using different definitions of NODAT, but one large study using fasting glucose and HbA1c found that 17% of kidney transplant recipients developed NODAT at 10 weeks [6]. The majority of cases are diagnosed in the first 3 months after transplantation, possibly because of the higher-level immunosuppression used at this time, but NODAT can also occur some years after renal transplantation. In a US study in 11 659 Medicare beneficiaries who received renal transplantation between 1996 and 2000, the incidence of diabetes after transplantation was 9.1, 16 and 24% at 3, 6 and 36 months respectively [13]. Inpatient hyperglycaemia after transplantation is associated with a fourfold increase in the development of NODAT [14]. There is a five-to-sixfold increase in incidence among transplant recipients during the first year after transplantation compared with that among people who remain on the transplant waiting list, which declines to an annual incidence of 4–6% after the first year [15]. The majority of people develop NODAT in the first 6 months after transplantation [10]. A more recent epidemiological study found that 30–37% of subjects developed NODAT within the first year after renal transplantation, based on a definition of the first occurrence of one of four parameters: (1) two fasting plasma glucose levels > 126 mg/dl (> 7.0 mmol/l) > 30 days apart; (2) oral hypoglycemic agent use for > 30 consecutive days; (3) insulin therapy for > 30 consecutive days; and (4) HbA1c > 48 mmol/mol (6.5%) [16].
Immunosuppressants
People undergoing transplantation are exposed to a unique set of diabetogenic risk factors of which immunosuppression
Table 2 Potential pathogenic/risk factors involved in the development of new-onset diabetes after transplantation Transplant-unrelated factors Age Ethnicity Obesity Genetics/Family history Presence of metabolic
syndrome Pre-transplant impaired
glucose tolerance or impaired fasting glucose Increased inflammatory
markers Adult polycystic kidney
disease Interstitial nephritis
Transplant-related factors
Pathogenesis of new-onset diabetes after transplantation The mechanism behind the development of NODAT in people not previously known to have diabetes is poorly understood. It is possible that a similar pathogenesis occurs to that of Type 2 diabetes, but differs in being partially
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Glucocorticoids Calcineurin inhibitors Hepatitis C virus infection Post-transplant weight gain
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is the most important. Immunosuppression is necessary to avoid allograft rejection and other transplant-related complications. Glucocorticoids are highly diabetogenic, primarily because of their effects on insulin resistance, enhanced gluconeogenesis, lipolysis-induced dyslipidaemia (elevated triglyceride and non-esterified fatty acids), and reduced glucose uptake in skeletal muscle. These effects appear to be dose-dependent, with a 5% increase in the risk of developing NODAT for every 0.01-mg/kg increase in prednisolone dose [21]. Whilst early withdrawal of steroids is desirable to reduce diabetes risk, this does appear to increase the risk of graft rejection. In fact one trial of early steroid withdrawal did not demonstrate a significant reduction in incidence of NODAT, although the group did have better glycaemic control and lower insulin requirements subsequently [22]. Calcineurin is critical to b-cell function and growth. Calcineurin inhibition leads to b-cell toxicity, and consequent impairment of insulin secretion, which is dose-related and potentially reversible. The mechanism behind this is not well defined, but animal models suggest that changes in cell signalling lead to diminished b-cell survival. Calcineurin inhibitors (tacrolimus, ciclosporin and voclosporin) inhibit T-lymphocyte activity by binding to specific intracellular target proteins. They can be nephrotoxic and neurotoxic, as well as cause metabolic problems such as hypertension, hyperlipidaemia and hyperglycaemia. Tacrolimus is more diabetogenic than ciclosporin; significantly more people receiving tacrolimus develop diabetes at 2 years compared with those not receiving the drug (31.8 vs 21.9%) [13,15]. The risk of developing diabetes after transplant is ~50% greater in people receiving tacrolimus compared with people not initially treated with the drug [13]. A Cochrane review concluded that treatment of 100 kidney transplant recipients with tacrolimus instead of ciclosporin avoided 12 episodes of acute rejection and two graft losses, but resulted in an extra five cases of insulin-requiring diabetes [23]. A newer calcineurin inhibitor, voclosporin, may be less diabetogenic, although this has not yet been fully established [24]. It was thought that mammalian target of rapamycin inhibitors, such as sirolimus, may have neutral effects on glucose levels, but some studies have shown these drugs to increase risk of post-transplant diabetes. Sirolimus is thought to cause abnormalities in glucose tolerance via impairment of insulin-mediated suppression of glycogenolysis, hypertriglyceride-induced insulin resistance and islet-cell toxicity [25]. Other antiproliferative agents such as mycophenolate mofetil and azathioprine have been suggested to lower risk of diabetes, possibly because of the lower doses of other immosuppressive agents required [13]. Combination therapy with sirolimus and either ciclosporin or tacrolimus appears to have the highest rate of NODAT at 12 months (21.9%), followed by tacrolimus and mycophenolate mofetil/azathioprine combinations (19%), sirolimus and mycophenolate mofetil/azathioprine (17.8%), with the lowest rate seen with
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a combination of ciclosporin and mycophenolate mofetil/ azathioprine (15.6%; P < 0.0001). Indeed, in a systematic review including 15 cohorts in 12 studies of people undergoing kidney transplantation, the type of immunosuppression regimen used (i.e steroids, ciclosporin, high- or low-dose tacrolimus) accounted for 74% of the variability in 12-month cumulative incidence of development of NODAT (P=0.0004) [26]. A newer agent used in the induction of immunosuppression, basiliximab, is associated with an increased risk of development of NODAT, with a relative risk of 2.3 (95% CI 1.4–3.9) [27]. Belatacept, however, appears to have a protective role against NODAT [28].
Risk factors for new-onset diabetes after transplantation
Traditional risk factors for Type 2 diabetes are well represented amongst people awaiting renal transplantation. People aged > 45 years undergoing transplantation have a 2.2-fold increased risk of developing NODAT, compared with those aged 18–44 years [13]. Non-white subjects experienced a twofold risk of developing NODAT compared with white subjects [26]. Genetics studies of NODAT have shown variable results, but loci implicated in NODAT include the interleukin(IL)-6 promoter gene, IL-7R, IL-17E, IL-17R and IL-17RB, as well as those genetic loci involved in increased risk for Type 2 diabetes [29]. Risk factors related to the transplant recipient include immunosuppressive drugs, the presence of cytomegalovirus or hepatitis C virus infection, and a possible association with the age and weight of the deceased kidney donor [10,13]. Hepatitis C seropositivity is an independent risk factor for NODAT, but this increased risk may be mitigated by pre-transplant treatment of hepatitis C virus with interferon and antiviral agents [13,17]. Several renal diseases appear to increase the risk of NODAT; autosomal dominant polycystic kidney disease and interstitial nephritis appear to be associated with a higher risk, whilst glomerulonephritis is associated with a lower risk [13,30]. The transplant recipient’s pre-transplant weight has a significant impact on the development of NODAT. In an analysis of Medicare renal transplant recipients, pre-transplant BMI > 30kg/m2 increased incidence of NODAT to 35.2%, compared with 21.8% in subjects with a BMI < 30kg/m2 [13]. Post-transplant weight gain is also important; for every 10 kg gained after transplant in people with a starting weight of 60 kg, the risk of NODAT increased by a factor of 1.4 [10,20]. The presence of metabolic syndrome pre-transplant is common (~57%) and is an independent risk factor for NODAT, with risk increasing with increasing number of components of metabolic syndrome [31]. Pre-transplant impaired fasting glucose and the development of postoperative hyperglycaemia in the first week are strongly predictive of subsequent development of NODAT [10,12,13]. A normal oral glucose tolerance test and fasting
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blood glucose on day 5 after transplantation appears to be associated with a reduced risk [32]. One study suggests that new hyperglycaemia (capillary blood glucose ≥ 200mg/dl [11.1 mmol/l]) developed by the patient during the postoperative hospital stay could be predicative of risk of developing NODAT in the future. That study reported that 4% of kidney transplant recipients without inpatient hyperglycaemia, 18% of inpatients with hyperglycaemia but not requiring insulin therapy and 30% of inpatients who required insulin therapy developed NODAT [14].
without diabetes [37]. Adjusting for sex, age and race, NODAT was found to be a significant independent predictor of graft failure (relative risk 3.72, P = 0.04). A large study using data from United States Renal Data System (USRDS) found NODAT to be an independent predictor of graft failure (relative risk 1.63, 95% CI 1.46–1.84; P < 0.0001), as well as death-censored graft failure (relative risk 1.46, 95% CI 1.25–1.70; P < 0.0001) [13]. A later analysis of 27 702 people from the same data registry, corroborated this finding (relative risk 1.24, 95% CI 1.14–1.35) [38]. A longitudinal study in Taiwan reported that people with NODAT have a twofold increase in the risk of reaching the primary outcome (doubling of serum creatinine, graft failure or death) in comparison with people without diabetes (relative risk 2, 95% CI 2.43–16.33; P < 0.001) [39]. A case–control study from the Cleveland Clinic showed a significant increase in graft rejection in people with NODAT in comparison with control subjects (47 vs 23%, P = 0.018) [40]. There are, however, some studies suggesting no impact of NODAT on graft survival. A retrospective study reported similar graft survival rates between people without diabetes and those who developed NODAT [41]. Data from the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database, found that NODAT was not associated with an increased risk of graft failure (adjusted hazard ratio 1.15, 95% CI, 0.97–1.37; P = 0.1) [42]. In that study, however, there was a relatively short follow-up (median follow-up 548 days). Longer-term follow up has also suggested similar 5- and 10-year graft survival rates between people with NODAT (87.4 and 76.7%, respectively) and those without diabetes (79.1 and 69.2%, respectively) [43]. More recently, no significant difference was observed in graft failure between NODAT and people without diabetes at 12, 24, 36, 48 and 60 months’ follow-up [44]. Whilst the link between graft survival and onset of NODAT is not fully established, the potential mechanisms underlying reduced graft survival in NODAT are also unclear.
Prediction of new-onset diabetes after transplantation
A number of prediction models have been used to estimate future risk of Type 2 diabetes in a non-transplant population. It is unclear whether these can be used to identify subjects at high risk of developing NODAT pre-transplantation. One study suggested that a pre-transplant score of ≥ 4 (using age, family history of Type 2 diabetes, BMI, fasting blood glucose, triglycerides, use of gout medications, use of post-transplant corticosteroids) predicted the incidence of NODAT at 1 year after transplant [33]. Use of standard risk scores such as the Framingham Offspring Study-Diabetes Mellitus (overweight/obesity, impaired fasting glucose, HDL cholesterol level, hypertriglyceridaemia, hypertension and family history) and the San Antonio Diabetes Predication model (age, sex, Mexican-American ethnicity, fasting glucose, systolic blood pressure, HDL cholesterol, BMI, family history of diabetes) could offer a high negative predicative value, but a low positive predicative value for risk of NODAT [8,34].
How does the diagnosis of new-onset diabetes after transplantation influence renal and other outcomes? Does new-onset diabetes after transplantation adversely affect graft survival?
Studies looking at the association of NODAT and graft survival have reported mixed results. The presence of metabolic syndrome has been suggested to be associated with an increased risk of graft failure post-transplant (hazard ratio 1.64, 95% CI 1.26–2.14; P = 0.0003), but in multivariate analysis adjusting for metabolic syndrome, NODAT, which develops as metabolic syndrome progresses, is associated with an even higher risk of graft failure (relative risk 1.63; 95% CI 1.18–2.24; P = 0.003), suggesting a possible dose–response relationship [35]. The increasing rates of NODAT between 1995 and 2002 and decreasing rates of acute rejection, both as a result of changes in immunosuppression regimens, make NODAT a potentially suitable surrogate marker for long-term graft failure [36]. In a prospective study, 12-year graft survival was 48% in those developing NODAT and 70% in the control group
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Does new-onset diabetes after transplantation adversely affect cardiovascular and other outcomes?
Development of NODAT may increase cardiovascular morbidity and mortality, although, again, data are conflicting. In a US registry study, NODAT was associated with an increased risk of death (relative risk 1.87, 95% CI 1.60– 2.18; P < 0.0001) [13]. In a further study, the 10-year survival rate was 75% in people without diabetes compared with 49% in those who developed NODAT [41]. Subjects aged < 55 years had an especially higher relative risk of death (relative risk 2.54, P < 0.001). These findings are corroborated by another study which found significant differences in the 5- and 10-year survival rates between people with NODAT (86.1 and 67.1%) and those without diabetes (90.9 and 81.9%) [43]. The survival rates after a diagnosis of
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NODAT was found to be similar to those for people with pre-existing diabetes, and both groups had worse survival rates than those without diabetes [10]. By contrast, one study found no significant difference in survival rate 12 years after transplant (subjects with diabetes 71%, control subjects 74%) [37]. A further survey reported an insignificant difference in survival between NODAT and people without diabetes (relative risk 0.63; 95% CI 0.13– 2.97; P = 0.562) [39]. The main cause of death in the post-transplant period is cardiovascular disease, irrespective of diabetes status. There is some evidence to suggest that NODAT is associated with an accelerated progression of some diabetes complications. One study found a dose–response relationship between level of hyperglycaemia after transplant and risk of cardiovascular disease (hazard ratio 1.05; P < 0.0001) [10]. The same study found cardiovascular disease risk to be greater in the NODAT group (hazard ratio 2.9; P = 0.01) and the impaired fasting glucose group (hazard ratio 2.4; P = 0.03), in comparison with the reference group (fasting glucose 5.0– 5.5 mmol/l). Additionally, the incidence of cardiovascular events was 23% in the NODAT group and 11% in people with euglycaemia. Estimates of the higher risk of cardiovascular disease in people with NODAT compared with those without diabetes suggest a significant increased risk (hazard ratio 1.86; 90% CI 1.43–2.43) [45]. There is a paucity of studies reporting on the development of microvascular complications in people with NODAT, although a higher risk of peripheral neuropathy has been reported [37]. Longer survival of transplant recipients may lead to a greater risk of the development of microvascular complications.
a group with impaired glucose tolerance/NODAT were treated with lifestyle modification and exercise advice. At 6 months, 44% of the impaired glucose tolerance group went on to have normal glucose tolerance, and 4% developed NODAT [48]. Pharmacological intervention in people at high risk of Type 2 diabetes, to reduce the risk of Type 2 diabetes is well established. In this regard, metformin, pioglitazone, acarbose and orlistat are all effective. These treatments have yet to be specifically tested to prevent NODAT. Treatment of hepatitis C virus pre-transplant with a-interferon therapy reduces the risk of NODAT [49]. Whilst statin therapy may be associated with a slight increased risk of the development of Type 2 diabetes, it is suggested that pre-transplant treatment with a statin reduces the incidence of NODAT [50]. Post-transplant use of isophane insulin has been shown to reduce the risk of developing NODAT by 73%, potentially via insulin-mediated protection of b cells [19]. Currently, at least two clinical trials (the SAPT-NODAT and the ITP-NODAT studies; Clinical Trials Registry nos NCT01680185 and NCT01683331, respectively) to assess the use of insulin post-transplant in a larger population are underway. Early use of oral anti-diabetic agents post-transplant may be effective, and at least two clinical trials are currently ongoing to test sitagliptin in the prevention of NODAT (Clinical Trials Registry nos NCT00936663 and NCT01928199). Recently, vildagliptin and pioglitazone have been shown to significantly lower HbA1c levels in comparison with placebo in people who have received a transplant (vildagliptin: 0.1% 0.3%; P = 0.046 and pioglitazone: 0.2% 0.3%; P = 0.029), and may be added to lifestyle interventions as preventative strategies against NODAT [51].
Prevention and management of new-onset diabetes after transplantation
Management of new-onset diabetes after transplantation
Can risk of new-onset diabetes after transplantation be reduced?
Lifestyle interventions have been shown to be effective at preventing or delaying the onset of Type 2 diabetes in a number of studies. Attempts to reduce the risk of development of NODAT may have to start at the phase of pre-transplantation, when the patient is receiving renal replacement therapy. Whilst early studies suggested a benefit of higher BMI on survival rate for those on dialysis, this may be attributable to higher muscle mass rather than fat mass [46]. It has therefore been postulated that pre-transplant interventions to improve muscle mass might decrease the incidence of NODAT. People with chronic kidney disease are more sedentary than those without, and hence lifestyle intervention may be effective in this group [47]. The effect of lifestyle modification on NODAT has been tested in a small study and may have an important beneficial effect. Amongst 115 renal transplant recipients,
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The recommendation that treatment of NODAT should follow the approach taken to treat Type 2 diabetes reflects a lack of studies assessing best management in NODAT. Currently treatment is based on expert opinion rather than evidence-based strategies [4]. Immunosuppression regimens
Whether changes in immunosuppression regimens can mitigate or reverse NODAT is unclear; there are no randomized controlled trials in this area, and reports supporting one regimen over another provide anecdotal evidence from uncontrolled studies. One study has shown that immediate conversion from tacrolimus to ciclosporin therapy ameliorated NODAT in 4/8 subjects whilst 3/8 completely discontinued anti-diabetic medication, without any effect on acute rejection or renal function [52]. Similarly, a switch to sirolimus from either tacrolimus or ciclosporin was associated with increased incidence of impaired glucose tolerance and NODAT [53]. An international guideline developed by the Kidney Disease: Improving Global Outcomes group [54],
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suggest the following changes which may ameliorate or reverse NODAT: (1) stop or reduce dose of tacrolimus, ciclosporin or corticosteroids; (2) if using tacrolimus-based therapy, consider a switch to ciclosporin, mycophenolate mofetil or azathioprine; (3) if using ciclosporin-based therapy, consider a switch to mycophenolate mofetil or azathioprine.
Table 3 Areas of uncertainty in the prevention, diagnosis and management of new-onset diabetes after transplantation Prevention Intensive lifestyle intervention to prevent
NODAT Use of risk scores to focus intervention to
prevent NODAT Use of risk scores to guide immuno
Anti-hyperglycaemic therapy
Amelioration and possibly reversal of NODAT through intensive lifestyle interventions have already been reported but may not be sustainable [48]. Additionally, the onset of NODAT and Type 2 diabetes are not comparable; NODAT tends to have a more acute onset, requiring early drug therapy rather than relying on lifestyle interventions to reduce hyperglycaemia. International consensus guidelines recommend a stepwise approach similar to that taken in the treatment of Type 2 diabetes [4]. There is a lack of randomized clinical trials to assess the effectiveness and safety of oral anti-diabetic drugs in NODAT, and most of their use is based on guidelines of therapy in Type 2 diabetes. Although metformin is the drug of first choice for the pharmacological treatment of diabetes, low estimated GFR early in the post-transplant phase makes early use of metformin in NODAT difficult, although not impossible with careful monitoring. The safety and efficacy of repaglinide, a prandial glucose regulator, and rosiglitazone, a thiazolidenedione, have been reported in observational studies [55]. A small study of sitagliptin, a dipeptidylpeptidase-4 inhibitor, has shown safety and efficacy in 15 people post-transplant over 3 months [56]. A clinical trial to assess the efficacy and safety of vildagliptin in people with NODAT has been completed and results are awaited (the Vildagliptin in New Onset Diabetes After Transplantation study; Clinical Trials Registry no. NCT00980356) [57]. Although expert opinion does not recommended sulphonylureas for the treatment of NODAT, gliquidone use has been reported to be safe, efficacious and free of interactions with immunosuppressive agents [58]. It has been suggested that sulphonylureas may exacerbate declining b-cell function, a hallmark of NODAT, but they may still be useful in dealing with acute hyperglycaemia in the early post-transplant phase. Acute, severe hyperglycaemia in the post-transplant phase may most safely be managed with insulin therapy, although there are no data on the optimum regimen to use. Screening for diabetes-related complications
Once diagnosed, people with NODAT should be referred for ongoing screening for complications, including retinal screening, and screening for foot complications [4]. Urine testing for microalbuminuria has not been validated as a marker of nephropathy in people with NODAT, and indeed individuals may have microalbuminuria without diabetes as a result of renal insufficiency or chronic rejection [4].
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suppression regimen to prevent NODAT Use of drugs pre-transplant to prevent
NODAT Diagnosis Use of regular post-meal glucose/capillary
glucose to diagnose NODAT Use of HbA1c to diagnose NODAT
Management Use of change in immunosuppression
regimen in early NODAT Use of oral hypoglycaemic agents in early
NODAT Optimum insulin regimens in NODAT
NODAT, new-onset diabetes after transplantation.
Management of NODAT microvascular complications is similar to that for people with Type 2 diabetes. Multidisciplinary management
Renal transplant recipients require intensive management of nephrological and other indices in the early post-transplant period, and subsequent lifelong follow-up. The onset of NODAT in renal transplant recipients heralds an increased risk of complications, with renal and cardiovascular morbidity increasing significantly. The management of NODAT may, therefore, be undertaken usefully in a joint multidisciplinary setting, involving nephrologists, diabetologists and specialist nursing/dietetic teams, in order to provide seamless care. A combined clinic allows such patients to undergo careful nephrological management, plus management and monitoring of diabetes and screening for diabetes complications.
Conclusions New-onset diabetes after transplantation is an important comorbidity in renal transplant recipients. The condition is common, and likely to be caused by a number of pre- and post-transplant-related factors, including pre- and post-transplant therapy, and patient-related risk factors for metabolic problems. The onset of hyperglycaemia after renal transplant appears to lead to increased risks, and these need careful management
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and monitoring to ensure renal and other complications do not ensue. The diagnosis, management and monitoring of people with NODAT is hampered by a lack of available clinical evidence, and whilst NODAT appears to be an important clinical entity, there are significant gaps in our knowledge of the condition. Some areas of uncertainty that need further research are listed in Table 3.
Funding sources
None.
Competing Interests
None declared.
References 1 Diabetes UK. Diabetes in the UK in 2010: Key Statistics on Diabetes 2011. Available at: http://www.diabetes.org.uk/Documents/Reports/ Diabetes_in_the_UK_2010.pdf. Last accessed 11 April 2014. 2 The Renal Association. UK Renal Registry 2009. Nephron Clin Pract 2010;115 (Suppl.1): c1–c370. 3 Starzl TE, Marchioro TL, Rifkind D, Holmes JH, Rowlands DT, Waddell WR. Factors in Successful Renal Transplantation. Surgery 1964; 56: 296–318. 4 Wilkinson A, Davidson J, Dotta F, Home PD, Keown P, Kiberd B et al. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005; 19: 291– 298. 5 World Health Organisation, 2011. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated report of a WHO consultation. WHO Geneva. Available at: http://www.who. int/diabetes/publications/report-hba1c_2011.pdf. Last accessed 11 April 2014. 6 Valderhaug TG, Jenssen T, Hartmann A, Midtvedt K, Holdaas H, Reisaeter AV et al. Fasting plasma glucose and glycosylated hemoglobin in the screening for diabetes mellitus after renal transplantation. Transplantation 2009; 88: 429–434. 7 Shabir S, Jham S, Harper L, Ball S, Borrows R, Sharif A. Validity of glycated haemoglobin to diagnose new onset diabetes after transplantation. Transpl Int 2013; 26: 315–321. 8 Pham PT, Edling KL, Chakkera HA, Pham PC, Pham PM. Screening strategies and predictive diagnostic tools for the development of new-onset diabetes mellitus after transplantation: an overview. Diabetes Metab Syndr Obes 2012; 5: 379–387. 9 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– 1672. 10 Cosio FG, Kudva Y, van der Velde M, Larson TS, Textor SC, Griffin MD et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 2005; 67: 2415–2421. 11 Yates CJ, Fourlanos S, Colman PG, Cohney SJ. Screening for new-onset diabetes after kidney transplantation: limitations of fasting glucose and advantages of afternoon glucose and glycated hemoglobin. Transplantation 2013; 96: 726–731. 12 Bergrem HA, Valderhaug TG, Hartmann A, Hjelmesaeth J, Leivestad T, Bergrem H et al. Undiagnosed diabetes in kidney transplant candidates: a case-finding strategy. Clin J Am Soc Nephrol 2010; 5: 616–622.
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13 Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178–185. 14 Chakkera HA, Knowler WC, Devarapalli Y, Weil EJ, Heilman RL, Dueck A et al. Relationship between inpatient hyperglycemia and insulin treatment after kidney transplantation and future new onset diabetes mellitus. Clin J Am Soc Nephrol 2010; 5: 1669– 1675. 15 Woodward RS et al. Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant 2003; 3: 590–598. 16 First MR, Dhadda S, Croy R, Holman J, Fitzsimmons WE. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation 2013; 96: 58–64. 17 Chakkera HA, Weil EJ, Pham PT, Pomeroy J, Knowler WC. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care 2013; 36: 1406–1412. 18 Zelle DM, Corpeleijn E, Deinum J, Stolk RP, Gans RO, Navis G et al. Pancreatic beta-cell dysfunction and risk of new-onset diabetes after kidney transplantation. Diabetes Care 2013; 36: 1926–1932. 19 Hecking M, Haidinger M, D€ oller D, Werzowa J, Tura A, Zhang J, Tekoglu H et al. Early basal insulin therapy decreases new-onset diabetes after renal transplantation. J Am Soc Nephrol 2012; 23: 739–749. 20 Bayes B, Granada ML, Pastor MC, Lauzurica R, Salinas I, Sanmartı A et al. Obesity, adiponectin and inflammation as predictors of new-onset diabetes mellitus after kidney transplantation. Am J Transplant 2007; 7: 416–422. 21 Hjelmesaeth J, Hartmann A, Kofstad J, Stenstrøm J, Leivestad T, Egeland T et al. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 1997; 64: 979–983. 22 Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248: 564–577. 23 Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005: CD003961. 24 Busque S, Cantarovich M, Mulgaonkar S, Gaston R, Gaber AO, Mayo PR, Ling S et al. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant 2011; 11: 2675– 2684. 25 Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19: 1411–1418. 26 Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002; 25: 583–592. 27 Prasad N, Gurjer D, Bhadauria D, Gupta A, Srivastava A, Kaul A et al. Is basiliximab induction, a novel risk factor for new onset diabetes after transplantation for living donor renal allograft recipients? Nephrology (Carlton) 2014; 19: 244–250. 28 Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Griny o J, Neumayer HH et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011; 91: 976–983. 29 Kim YG, Ihm CG, Lee TW, Lee SH, Jeong KH, Moon JY, Chung JH et al. Association of genetic polymorphisms of interleukins with new-onset diabetes after transplantation in renal transplantation. Transplantation 2012; 93: 900–907.
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30 Hamer RA, Chow CL, Ong AC, McKane WS. Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation. Transplantation 2007; 83: 36–40. 31 Bayer ND, Cochetti PT, Anil Kumar MS, Teal V, Huan Y, Doria C et al. Association of metabolic syndrome with development of new-onset diabetes after transplantation. Transplantation 2010; 90: 861–866. 32 Kuypers DR, Claes K, Bammens B, Evenepoel P, Vanrenterghem Y. Early clinical assessment of glucose metabolism in renal allograft recipients: diagnosis and prediction of post-transplant diabetes mellitus (PTDM). Nephrol Dial Transplant 2008; 23: 2033–2042. 33 Chakkera HA, Weil EJ, Swanson CM, Dueck AC, Heilman RL, Reddy KS et al. Pretransplant risk score for new-onset diabetes after kidney transplantation. Diabetes Care 2011; 34: 2141–2145. 34 Rodrigo E, Santos L, Pi~ nera C, Millan JC, Quintela ME, Toyos C et al. Prediction at first year of incident new-onset diabetes after kidney transplantation by risk prediction models. Diabetes Care 2012; 35: 471–473. 35 Israni AK, Snyder JJ, Skeans MA, Kasiske BL. PORT Investigators. Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. Transpl Int 2012; 25: 748–757. 36 Sharif A, Baboolal K. Complications associated with new-onset diabetes after kidney transplantation. Nat Rev Nephrol 2012; 8: 34–42. 37 Miles AM, Sumrani N, Horowitz R, Homel P, Maursky V, Markell MS et al. Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes? Transplantation 1998; 65: 380–384. 38 Matas AJ, Gillingham KJ, Humar A, Ibrahim HN, Payne WD, Gruessner RW et al. Post-transplant diabetes mellitus and acute rejection: impact on kidney transplant outcome. Transplantation 2008; 85: 338–343. 39 Tsai JP, Lian JD, Wu SW, Hung TW, Tsai HC, Chang HR. Long-term impact of pretransplant and post-transplant diabetes mellitus on kidney transplant outcomes. World J Surg 2011; 35: 2818–2125. 40 Siraj ES, Abacan C, Chinnappa P, Wojtowicz J, Braun W. Risk factors and outcomes associated with post-transplant diabetes mellitus in kidney transplant recipients. Transplant Proc 2010; 42: 1685–1689. 41 Revanur VK, Jardine AG, Kingsmore DB, Jaques BC, Hamilton DH, Jindal RM. Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation. Clin Transplant 2001; 15: 89–94. 42 Kuo HT, Sampaio MS, Vincenti F, Bunnapradist S. Associations of pretransplant diabetes mellitus, new-onset diabetes after transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database. Am J Kidney Dis 2010; 56: 1127–1139. 43 Joss N, Staatz CE, Thomson AH, Jardine AG. Predictors of new onset diabetes after renal transplantation. Clin Transplant 2007; 21: 136–143. 44 Cotovio P, Neves M, Rodrigues L, Alves R, Bastos M, Baptista C et al. New-onset diabetes after transplantation: assessment of risk factors and clinical outcomes. Transplant Proc 2013; 45: 1079–1083.
45 Israni AK, Snyder JJ, Skeans MA, Peng Y, Maclean JR, Weinhandl ED et al. Predicting coronary heart disease after kidney transplantation: Patient Outcomes in Renal Transplantation (PORT) Study. Am J Transplant 2010; 10: 338–353. 46 Leavey SF, McCullough K, Hecking E, Goodkin D, Port FK, Young EW. Body mass index and mortality in ‘healthier’ as compared with ‘sicker’ haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2001; 16: 2386–2394. 47 Painter P, Ward K, Nelson RD. Self-reported physical activity in patients with end stage renal disease. Nephrol Nurs J 2011; 38: 139–147. 48 Sharif A, Moore R, Baboolal K. Influence of lifestyle modification in renal transplant recipients with postprandial hyperglycemia. Transplantation 2008; 85: 353–358. 49 Kamar N, Toupance O, Buchler M, Sandres-Saune K, Izopet J, Durand D et al. Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. J Am Soc Nephrol 2003; 14: 2092–2098. 50 Prasad GVR, Kim SJ, Huang M, Nash MM, Zaltzman JS, Fenton SS et al. Reduced Incidence of New-Onset Diabetes Mellitus after Renal Transplantation with 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins). Am J Transplant 2004; 4: 1897–1903. 51 Werzowa J, Hecking M, Haidinger M, Lechner F, D€ oller D, Pacini G et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation: a randomized, placebo-controlled clinical trial. Transplantation 2013; 95: 456– 462. 52 Oberholzer J, Thielke J, Hatipoglu B, Testa G, Sankary HN, Benedetti E. Immediate conversion from tacrolimus to cyclosporine in the treatment of posttransplantation diabetes mellitus. Transplant Proc 2005; 37: 999–1000. 53 Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005; 16: 3128– 3135. 54 Madsen JC. KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Trans 2009; 9: S1–S155. 55 Turk T, Pietruck F, Dolff S, Kribben A, Janssen OE, Mann K et al. Repaglinide in the management of new-onset diabetes mellitus after renal transplantation. Am J Transplant 2006; 6: 842–846. 56 Lane JT, Odegaard DE, Haire CE, Collier DS, Wrenshall LE, Stevens RB et al. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation 2011; 92: e56–57. 57 Haidinger M, Werzowa J, Voigt HC, Pleiner J, Stemer G, Hecking M et al. A randomized, placebo-controlled, double-blind, prospective trial to evaluate the effect of vildagliptin in new-onset diabetes mellitus after kidney transplantation. Trials 2010; 11: 91. 58 Ghisdal L, Van Laecke S, Abramowicz MJ, Vanholder R, Abramowicz D. New-Onset Diabetes After Renal Transplantation: Risk assessment and management. Diabetes Care 2012; 35: 181– 188.
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Review Article New-onset diabetes after renal transplantation N. Tufton1, S. Ahmad1, C. Rolfe2, R. Rajkariar2, C. Byrne2 and T. A. Chowdhury1 1 Department of Diabetes and Metabolism, Barts and the London School of Medicine and Dentistry, London, UK and 2Department of Nephrology, Barts and the London School of Medicine and Dentistry, London, UK
Accepted 24 June 2014
Abstract Renal transplantation has important benefits in people with end-stage renal disease, with improvements in mortality, morbidity and quality of life. Whilst significant advances in transplantation techniques and immunosuppressive regimens have led to improvements in short-term outcomes, longer-term outcomes have not improved dramatically. New-onset diabetes after transplantation appears to be a major factor in morbidity and cardiovascular mortality in renal transplant recipients. The diagnosis of new-onset diabetes after renal transplantation has been hampered by a lack of clarity over diagnostic tests in early studies, although the use of the WHO criteria is now generally accepted. HbA1c may be useful diagnostically, but should probably be avoided in the first 3 months after transplantation. The pathogenesis of new-onset diabetes after renal transplantation is likely to be related to standard pathogenic factors in Type 2 diabetes (e.g. insulin resistance, b-cell failure, inflammation and genetic factors) as well as other factors, such as hepatitis C infection, and could be exacerbated by the use of immunosuppression (glucocorticoids and calcineurin inhibitors). Pre-transplant risk scores may help identify those people at risk of new-onset diabetes after renal transplantation. There are no randomized trials of treatment of new-onset diabetes after renal transplantation to determine whether intensive glucose control has an impact on cardiovascular or renal morbidity, therefore, treatment is guided by guidelines used in non-transplant diabetes. Many areas of uncertainty in the pathogenesis, diagnosis and management of new-onset diabetes after renal transplantation require further research. Diabet. Med. 31, 1284–1292 (2014)
Introduction Diabetes mellitus is a pressing public health issue as a result of its increasing prevalence and associated high social and economic costs. In the UK in 2013, ~10% of healthcare spending was directly related to diabetes or its attendant complications [1]. Diabetes complications are multi-system and are placing an increasing burden on cardiovascular, renal, ophthalmological, podiatric and vascular services. Renal disease accounts for ~20% of deaths in people with Type 1 diabetes and 10% of deaths in Type 2 diabetes, and there are currently nearly 7000 people with diabetes on the UK dialysis or transplant programme [2]. Renal transplantation has a proven clinical benefit in people with end-stage renal failure. Whilst diabetes is a common cause of end-stage renal failure, new-onset diabetes after transplantation (NODAT) can be a significant complication of renal transplantation. The condition may have adverse effects on renal and other outcomes after renal transplantation. The Correspondence to: Tahseen A. Chowdhury. E-mail: [email protected]
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present review focuses on the current knowledge of the pathogenesis, risk factors and management of this specific form of diabetes amongst people with renal disease.
Search strategy and selection criteria We searched the Medline database up to 16 December 2013 for the terms ‘diabetes’ and ‘renal transplantation’, or ‘new-onset diabetes after transplantation’ with emphasis on publications from the last 10 years, although seminal older publications were also included. Articles from the reference list of these publications were also considered.
What is new-onset diabetes after transplantation and how common is the condition? Diagnosis
New-onset diabetes after transplantation as a complication of renal transplantation was first described in 1964 [3], and
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has more recently been recognized as having an important impact on cardiovascular and renal morbidity. NODAT refers to the occurrence of diabetes in a person after organ transplantation who was previously not known to have diabetes, and has been reported after transplants of kidney, liver, lung and heart, as well as bone marrow and haemopoietic stem cells. A number of definitions have been suggested since its recognition, including ‘the uninterrupted need for glucose-lowering therapy for at least 3 months after transplantation’, ‘the use of insulin postoperatively’, ‘the need for oral agents’ and ‘fasting glucose values between 7 and 13mmol/l’. International consensus guidelines published in 2003, and updated in 2004 used the WHO and American Diabetes Association guidance on diagnosis of diabetes mellitus and impaired glucose tolerance [4]. These diagnostic criteria incorporate symptoms, fasting glucose measurements and 2-h postprandial readings after an oral glucose tolerance test (Table 1). Individuals with fasting glucose values of 6.1–6.9 mmol/l (110–125mg/dl) are defined as having impaired fasting glucose and those with 2-h glucose values of 7.8–11.1 mmol/l (140–199mg/dl) after an oral glucose tolerance test are defined as having impaired glucose tolerance. Both conditions are associated with an increased risk of developing diabetes and cardiovascular disease. More recently, the WHO has suggested that HbA1c can be used to diagnose diabetes in a general population, with a diagnostic level of ≥ 48 mmol/mol (6.5%) on two occasions in an asymptomatic individual [5]. In renal transplantation, HbA1c should probably not be used < 3 months after transplant, as the test may not be accurate before adequate time is allowed for synthesis and glycation of new haemoglobin in the post-transplant period. One study has suggested that an HbA1c level > 39 mmol/mol (5.7%) at 10 weeks can identify the need for oral glucose tolerance test assessment, with a 91% sensitivity [6]. A further study has suggested that an HbA1c level > 44 mmol/mol (6.2%) at 3 months after transplant (sensitivity 100% and specificity 88.9%) and a level of 47 mmol/mol (6.45%) at 12 months (sensitivity 100% and specificity 87.5%) are useful thresholds, and concluded that HbA1c ≥ 48 mmol/mol (6.5%) could be used
to diagnose NODAT at least 3 months after transplantation [7]. The validity of using HbA1c for routine screening or as a diagnostic tool is yet to be validated because of significant ethnic variation, and its value as a pre-transplant screening tool is also unclear. Some studies suggest that postprandial glucose may be useful diagnostically [7–9], although there is evidence to suggest that increasing levels of fasting glycaemia are associated with increasing risk of cardiovascular events after transplantation [10]. A recent study compared diagnostic criteria at different time points after transplantation [11]. Of the 26 people screened at 6 weeks after transplant, NODAT was detected in 46% using capillary blood glucose, vs 4% using HbA1c, 12% using an oral glucose tolerance test, and 0% using fasting plasma glucose. At 3 months, NODAT was detected in 14% by HbA1c vs 20% with oral glucose tolerance test and 2% with fasting plasma glucose, with the corresponding figures at 12 months being 4, 6 and 2%. This suggests that fasting plasma glucose has significant limitations diagnostically, possibly as a result of calcineurin inhibitors/steroid-based immunosuppression drugs inducing postprandial peaks in glucose rather than fasting hyperglycaemia. The use of an oral glucose tolerance test before transplantation has been evaluated as a screening tool to identify people at high risk of developing NODAT [12]. In a predominantly white population, one such study found 8.1% of a pre-transplant population had undiagnosed diabetes, and 78% of these would have been missed if only fasting blood glucose had been used. The 2004 updated guidelines on the screening and management of NODAT recommend performing an oral glucose tolerance test in those with intermediate fasting glucose (110–125 mg/dl, 6.1–6.9 mmol/l) and HbA1c testing to be included as part of screening after the initial 3-month period has elapsed, as well as taking a full personal and family glucose history and screening for other components of metabolic syndrome in pre-transplantation consultations [4]. It is also notable that post-transplantation hyperglycaemia and diabetes can be a transient phenomenon, so although such individuals may be labelled as having diabetes
Table 1 Diagnostic criteria, according to the WHO, for new-onset diabetes after transplantation
Diabetes Random plasma glucose
Fasting plasma glucose 2-h plasma glucose after 75 g glucose HbA1c (not yet considered diagnostic in the immediate post-transplant period)
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11.1 mmol/l (200 mg/dl)+Symptoms (polyuria, polydipsia, weight loss, tiredness) ≥ 7.0 mmol/l (≥ 126 mg/dl) ≥ 11.1 mmol/l (200 mg/dl) > 6.5% (48 mmol/mol)
Impaired fasting glucose
Impaired glucose tolerance
–
–
6.1–6.9 mmol/l (110–125 mg/dl) – –
– 7.8–11.0 mmol/l (140–199 mg/dl) Pre-diabetes:42–47 mmol/mol (6.0–6.4%)
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using the above criteria, this may subsequently resolve, but they remain at a higher risk of developing diabetes in the future [10]. Conversely, any individual identified with impaired glucose tolerance should be monitored more closely after transplant because of their high risk of developing NODAT [4].
reversible because of the associated immunosuppressive medications (Table 2) [17]. Similarly to Type 2 diabetes, peripheral insulin resistance and impaired insulin secretion have been implicated in the development of NODAT. b-cell dysfunction appears to play an important role [18], as demonstrated by the fact that early aggressive treatment of hyperglycaemia in the early post-transplant period may have a protective effect against NODAT [19]. Insulin resistance tends to increase after transplantation as a result of drug therapy, including steroids and calcineurin inhibitors. Calcineurin inhibitors may affect both insulin sensitivity and insulin secretion by a variety of ill-defined mechanisms (see below). Unsurprisingly, pre-transplant obesity, inflammation and markers of insulin resistance appear to be risk markers for NODAT. Some investigators have shown that low levels of adiponectin (an adipocytokine which enhances insulin sensitivity), high concentrations of C-reactive protein, high triglyceride levels and elevated BMI before transplant predict the development of NODAT [20].
Epidemiology
Undiagnosed diabetes is common among people awaiting renal transplantation. One large study in white people on the waiting list for renal transplantation found that 8% of people had undiagnosed diabetes based on fasting or 2-h blood glucose readings, and 37% had impaired fasting glucose or impaired glucose tolerance [12]. The reported incidence of NODAT, however, varies widely between studies, with anywhere between 2 and 53% of renal transplant recipients developing diabetes in the first year after transplant. The wide range of incidence reported may be attributable to different diagnostic criteria, with many studies using different definitions of NODAT, but one large study using fasting glucose and HbA1c found that 17% of kidney transplant recipients developed NODAT at 10 weeks [6]. The majority of cases are diagnosed in the first 3 months after transplantation, possibly because of the higher-level immunosuppression used at this time, but NODAT can also occur some years after renal transplantation. In a US study in 11 659 Medicare beneficiaries who received renal transplantation between 1996 and 2000, the incidence of diabetes after transplantation was 9.1, 16 and 24% at 3, 6 and 36 months respectively [13]. Inpatient hyperglycaemia after transplantation is associated with a fourfold increase in the development of NODAT [14]. There is a five-to-sixfold increase in incidence among transplant recipients during the first year after transplantation compared with that among people who remain on the transplant waiting list, which declines to an annual incidence of 4–6% after the first year [15]. The majority of people develop NODAT in the first 6 months after transplantation [10]. A more recent epidemiological study found that 30–37% of subjects developed NODAT within the first year after renal transplantation, based on a definition of the first occurrence of one of four parameters: (1) two fasting plasma glucose levels > 126 mg/dl (> 7.0 mmol/l) > 30 days apart; (2) oral hypoglycemic agent use for > 30 consecutive days; (3) insulin therapy for > 30 consecutive days; and (4) HbA1c > 48 mmol/mol (6.5%) [16].
Immunosuppressants
People undergoing transplantation are exposed to a unique set of diabetogenic risk factors of which immunosuppression
Table 2 Potential pathogenic/risk factors involved in the development of new-onset diabetes after transplantation Transplant-unrelated factors Age Ethnicity Obesity Genetics/Family history Presence of metabolic
syndrome Pre-transplant impaired
glucose tolerance or impaired fasting glucose Increased inflammatory
markers Adult polycystic kidney
disease Interstitial nephritis
Transplant-related factors
Pathogenesis of new-onset diabetes after transplantation The mechanism behind the development of NODAT in people not previously known to have diabetes is poorly understood. It is possible that a similar pathogenesis occurs to that of Type 2 diabetes, but differs in being partially
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Glucocorticoids Calcineurin inhibitors Hepatitis C virus infection Post-transplant weight gain
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is the most important. Immunosuppression is necessary to avoid allograft rejection and other transplant-related complications. Glucocorticoids are highly diabetogenic, primarily because of their effects on insulin resistance, enhanced gluconeogenesis, lipolysis-induced dyslipidaemia (elevated triglyceride and non-esterified fatty acids), and reduced glucose uptake in skeletal muscle. These effects appear to be dose-dependent, with a 5% increase in the risk of developing NODAT for every 0.01-mg/kg increase in prednisolone dose [21]. Whilst early withdrawal of steroids is desirable to reduce diabetes risk, this does appear to increase the risk of graft rejection. In fact one trial of early steroid withdrawal did not demonstrate a significant reduction in incidence of NODAT, although the group did have better glycaemic control and lower insulin requirements subsequently [22]. Calcineurin is critical to b-cell function and growth. Calcineurin inhibition leads to b-cell toxicity, and consequent impairment of insulin secretion, which is dose-related and potentially reversible. The mechanism behind this is not well defined, but animal models suggest that changes in cell signalling lead to diminished b-cell survival. Calcineurin inhibitors (tacrolimus, ciclosporin and voclosporin) inhibit T-lymphocyte activity by binding to specific intracellular target proteins. They can be nephrotoxic and neurotoxic, as well as cause metabolic problems such as hypertension, hyperlipidaemia and hyperglycaemia. Tacrolimus is more diabetogenic than ciclosporin; significantly more people receiving tacrolimus develop diabetes at 2 years compared with those not receiving the drug (31.8 vs 21.9%) [13,15]. The risk of developing diabetes after transplant is ~50% greater in people receiving tacrolimus compared with people not initially treated with the drug [13]. A Cochrane review concluded that treatment of 100 kidney transplant recipients with tacrolimus instead of ciclosporin avoided 12 episodes of acute rejection and two graft losses, but resulted in an extra five cases of insulin-requiring diabetes [23]. A newer calcineurin inhibitor, voclosporin, may be less diabetogenic, although this has not yet been fully established [24]. It was thought that mammalian target of rapamycin inhibitors, such as sirolimus, may have neutral effects on glucose levels, but some studies have shown these drugs to increase risk of post-transplant diabetes. Sirolimus is thought to cause abnormalities in glucose tolerance via impairment of insulin-mediated suppression of glycogenolysis, hypertriglyceride-induced insulin resistance and islet-cell toxicity [25]. Other antiproliferative agents such as mycophenolate mofetil and azathioprine have been suggested to lower risk of diabetes, possibly because of the lower doses of other immosuppressive agents required [13]. Combination therapy with sirolimus and either ciclosporin or tacrolimus appears to have the highest rate of NODAT at 12 months (21.9%), followed by tacrolimus and mycophenolate mofetil/azathioprine combinations (19%), sirolimus and mycophenolate mofetil/azathioprine (17.8%), with the lowest rate seen with
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a combination of ciclosporin and mycophenolate mofetil/ azathioprine (15.6%; P < 0.0001). Indeed, in a systematic review including 15 cohorts in 12 studies of people undergoing kidney transplantation, the type of immunosuppression regimen used (i.e steroids, ciclosporin, high- or low-dose tacrolimus) accounted for 74% of the variability in 12-month cumulative incidence of development of NODAT (P=0.0004) [26]. A newer agent used in the induction of immunosuppression, basiliximab, is associated with an increased risk of development of NODAT, with a relative risk of 2.3 (95% CI 1.4–3.9) [27]. Belatacept, however, appears to have a protective role against NODAT [28].
Risk factors for new-onset diabetes after transplantation
Traditional risk factors for Type 2 diabetes are well represented amongst people awaiting renal transplantation. People aged > 45 years undergoing transplantation have a 2.2-fold increased risk of developing NODAT, compared with those aged 18–44 years [13]. Non-white subjects experienced a twofold risk of developing NODAT compared with white subjects [26]. Genetics studies of NODAT have shown variable results, but loci implicated in NODAT include the interleukin(IL)-6 promoter gene, IL-7R, IL-17E, IL-17R and IL-17RB, as well as those genetic loci involved in increased risk for Type 2 diabetes [29]. Risk factors related to the transplant recipient include immunosuppressive drugs, the presence of cytomegalovirus or hepatitis C virus infection, and a possible association with the age and weight of the deceased kidney donor [10,13]. Hepatitis C seropositivity is an independent risk factor for NODAT, but this increased risk may be mitigated by pre-transplant treatment of hepatitis C virus with interferon and antiviral agents [13,17]. Several renal diseases appear to increase the risk of NODAT; autosomal dominant polycystic kidney disease and interstitial nephritis appear to be associated with a higher risk, whilst glomerulonephritis is associated with a lower risk [13,30]. The transplant recipient’s pre-transplant weight has a significant impact on the development of NODAT. In an analysis of Medicare renal transplant recipients, pre-transplant BMI > 30kg/m2 increased incidence of NODAT to 35.2%, compared with 21.8% in subjects with a BMI < 30kg/m2 [13]. Post-transplant weight gain is also important; for every 10 kg gained after transplant in people with a starting weight of 60 kg, the risk of NODAT increased by a factor of 1.4 [10,20]. The presence of metabolic syndrome pre-transplant is common (~57%) and is an independent risk factor for NODAT, with risk increasing with increasing number of components of metabolic syndrome [31]. Pre-transplant impaired fasting glucose and the development of postoperative hyperglycaemia in the first week are strongly predictive of subsequent development of NODAT [10,12,13]. A normal oral glucose tolerance test and fasting
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blood glucose on day 5 after transplantation appears to be associated with a reduced risk [32]. One study suggests that new hyperglycaemia (capillary blood glucose ≥ 200mg/dl [11.1 mmol/l]) developed by the patient during the postoperative hospital stay could be predicative of risk of developing NODAT in the future. That study reported that 4% of kidney transplant recipients without inpatient hyperglycaemia, 18% of inpatients with hyperglycaemia but not requiring insulin therapy and 30% of inpatients who required insulin therapy developed NODAT [14].
without diabetes [37]. Adjusting for sex, age and race, NODAT was found to be a significant independent predictor of graft failure (relative risk 3.72, P = 0.04). A large study using data from United States Renal Data System (USRDS) found NODAT to be an independent predictor of graft failure (relative risk 1.63, 95% CI 1.46–1.84; P < 0.0001), as well as death-censored graft failure (relative risk 1.46, 95% CI 1.25–1.70; P < 0.0001) [13]. A later analysis of 27 702 people from the same data registry, corroborated this finding (relative risk 1.24, 95% CI 1.14–1.35) [38]. A longitudinal study in Taiwan reported that people with NODAT have a twofold increase in the risk of reaching the primary outcome (doubling of serum creatinine, graft failure or death) in comparison with people without diabetes (relative risk 2, 95% CI 2.43–16.33; P < 0.001) [39]. A case–control study from the Cleveland Clinic showed a significant increase in graft rejection in people with NODAT in comparison with control subjects (47 vs 23%, P = 0.018) [40]. There are, however, some studies suggesting no impact of NODAT on graft survival. A retrospective study reported similar graft survival rates between people without diabetes and those who developed NODAT [41]. Data from the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database, found that NODAT was not associated with an increased risk of graft failure (adjusted hazard ratio 1.15, 95% CI, 0.97–1.37; P = 0.1) [42]. In that study, however, there was a relatively short follow-up (median follow-up 548 days). Longer-term follow up has also suggested similar 5- and 10-year graft survival rates between people with NODAT (87.4 and 76.7%, respectively) and those without diabetes (79.1 and 69.2%, respectively) [43]. More recently, no significant difference was observed in graft failure between NODAT and people without diabetes at 12, 24, 36, 48 and 60 months’ follow-up [44]. Whilst the link between graft survival and onset of NODAT is not fully established, the potential mechanisms underlying reduced graft survival in NODAT are also unclear.
Prediction of new-onset diabetes after transplantation
A number of prediction models have been used to estimate future risk of Type 2 diabetes in a non-transplant population. It is unclear whether these can be used to identify subjects at high risk of developing NODAT pre-transplantation. One study suggested that a pre-transplant score of ≥ 4 (using age, family history of Type 2 diabetes, BMI, fasting blood glucose, triglycerides, use of gout medications, use of post-transplant corticosteroids) predicted the incidence of NODAT at 1 year after transplant [33]. Use of standard risk scores such as the Framingham Offspring Study-Diabetes Mellitus (overweight/obesity, impaired fasting glucose, HDL cholesterol level, hypertriglyceridaemia, hypertension and family history) and the San Antonio Diabetes Predication model (age, sex, Mexican-American ethnicity, fasting glucose, systolic blood pressure, HDL cholesterol, BMI, family history of diabetes) could offer a high negative predicative value, but a low positive predicative value for risk of NODAT [8,34].
How does the diagnosis of new-onset diabetes after transplantation influence renal and other outcomes? Does new-onset diabetes after transplantation adversely affect graft survival?
Studies looking at the association of NODAT and graft survival have reported mixed results. The presence of metabolic syndrome has been suggested to be associated with an increased risk of graft failure post-transplant (hazard ratio 1.64, 95% CI 1.26–2.14; P = 0.0003), but in multivariate analysis adjusting for metabolic syndrome, NODAT, which develops as metabolic syndrome progresses, is associated with an even higher risk of graft failure (relative risk 1.63; 95% CI 1.18–2.24; P = 0.003), suggesting a possible dose–response relationship [35]. The increasing rates of NODAT between 1995 and 2002 and decreasing rates of acute rejection, both as a result of changes in immunosuppression regimens, make NODAT a potentially suitable surrogate marker for long-term graft failure [36]. In a prospective study, 12-year graft survival was 48% in those developing NODAT and 70% in the control group
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Does new-onset diabetes after transplantation adversely affect cardiovascular and other outcomes?
Development of NODAT may increase cardiovascular morbidity and mortality, although, again, data are conflicting. In a US registry study, NODAT was associated with an increased risk of death (relative risk 1.87, 95% CI 1.60– 2.18; P < 0.0001) [13]. In a further study, the 10-year survival rate was 75% in people without diabetes compared with 49% in those who developed NODAT [41]. Subjects aged < 55 years had an especially higher relative risk of death (relative risk 2.54, P < 0.001). These findings are corroborated by another study which found significant differences in the 5- and 10-year survival rates between people with NODAT (86.1 and 67.1%) and those without diabetes (90.9 and 81.9%) [43]. The survival rates after a diagnosis of
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NODAT was found to be similar to those for people with pre-existing diabetes, and both groups had worse survival rates than those without diabetes [10]. By contrast, one study found no significant difference in survival rate 12 years after transplant (subjects with diabetes 71%, control subjects 74%) [37]. A further survey reported an insignificant difference in survival between NODAT and people without diabetes (relative risk 0.63; 95% CI 0.13– 2.97; P = 0.562) [39]. The main cause of death in the post-transplant period is cardiovascular disease, irrespective of diabetes status. There is some evidence to suggest that NODAT is associated with an accelerated progression of some diabetes complications. One study found a dose–response relationship between level of hyperglycaemia after transplant and risk of cardiovascular disease (hazard ratio 1.05; P < 0.0001) [10]. The same study found cardiovascular disease risk to be greater in the NODAT group (hazard ratio 2.9; P = 0.01) and the impaired fasting glucose group (hazard ratio 2.4; P = 0.03), in comparison with the reference group (fasting glucose 5.0– 5.5 mmol/l). Additionally, the incidence of cardiovascular events was 23% in the NODAT group and 11% in people with euglycaemia. Estimates of the higher risk of cardiovascular disease in people with NODAT compared with those without diabetes suggest a significant increased risk (hazard ratio 1.86; 90% CI 1.43–2.43) [45]. There is a paucity of studies reporting on the development of microvascular complications in people with NODAT, although a higher risk of peripheral neuropathy has been reported [37]. Longer survival of transplant recipients may lead to a greater risk of the development of microvascular complications.
a group with impaired glucose tolerance/NODAT were treated with lifestyle modification and exercise advice. At 6 months, 44% of the impaired glucose tolerance group went on to have normal glucose tolerance, and 4% developed NODAT [48]. Pharmacological intervention in people at high risk of Type 2 diabetes, to reduce the risk of Type 2 diabetes is well established. In this regard, metformin, pioglitazone, acarbose and orlistat are all effective. These treatments have yet to be specifically tested to prevent NODAT. Treatment of hepatitis C virus pre-transplant with a-interferon therapy reduces the risk of NODAT [49]. Whilst statin therapy may be associated with a slight increased risk of the development of Type 2 diabetes, it is suggested that pre-transplant treatment with a statin reduces the incidence of NODAT [50]. Post-transplant use of isophane insulin has been shown to reduce the risk of developing NODAT by 73%, potentially via insulin-mediated protection of b cells [19]. Currently, at least two clinical trials (the SAPT-NODAT and the ITP-NODAT studies; Clinical Trials Registry nos NCT01680185 and NCT01683331, respectively) to assess the use of insulin post-transplant in a larger population are underway. Early use of oral anti-diabetic agents post-transplant may be effective, and at least two clinical trials are currently ongoing to test sitagliptin in the prevention of NODAT (Clinical Trials Registry nos NCT00936663 and NCT01928199). Recently, vildagliptin and pioglitazone have been shown to significantly lower HbA1c levels in comparison with placebo in people who have received a transplant (vildagliptin: 0.1% 0.3%; P = 0.046 and pioglitazone: 0.2% 0.3%; P = 0.029), and may be added to lifestyle interventions as preventative strategies against NODAT [51].
Prevention and management of new-onset diabetes after transplantation
Management of new-onset diabetes after transplantation
Can risk of new-onset diabetes after transplantation be reduced?
Lifestyle interventions have been shown to be effective at preventing or delaying the onset of Type 2 diabetes in a number of studies. Attempts to reduce the risk of development of NODAT may have to start at the phase of pre-transplantation, when the patient is receiving renal replacement therapy. Whilst early studies suggested a benefit of higher BMI on survival rate for those on dialysis, this may be attributable to higher muscle mass rather than fat mass [46]. It has therefore been postulated that pre-transplant interventions to improve muscle mass might decrease the incidence of NODAT. People with chronic kidney disease are more sedentary than those without, and hence lifestyle intervention may be effective in this group [47]. The effect of lifestyle modification on NODAT has been tested in a small study and may have an important beneficial effect. Amongst 115 renal transplant recipients,
ª 2014 The Authors. Diabetic Medicine ª 2014 Diabetes UK
The recommendation that treatment of NODAT should follow the approach taken to treat Type 2 diabetes reflects a lack of studies assessing best management in NODAT. Currently treatment is based on expert opinion rather than evidence-based strategies [4]. Immunosuppression regimens
Whether changes in immunosuppression regimens can mitigate or reverse NODAT is unclear; there are no randomized controlled trials in this area, and reports supporting one regimen over another provide anecdotal evidence from uncontrolled studies. One study has shown that immediate conversion from tacrolimus to ciclosporin therapy ameliorated NODAT in 4/8 subjects whilst 3/8 completely discontinued anti-diabetic medication, without any effect on acute rejection or renal function [52]. Similarly, a switch to sirolimus from either tacrolimus or ciclosporin was associated with increased incidence of impaired glucose tolerance and NODAT [53]. An international guideline developed by the Kidney Disease: Improving Global Outcomes group [54],
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suggest the following changes which may ameliorate or reverse NODAT: (1) stop or reduce dose of tacrolimus, ciclosporin or corticosteroids; (2) if using tacrolimus-based therapy, consider a switch to ciclosporin, mycophenolate mofetil or azathioprine; (3) if using ciclosporin-based therapy, consider a switch to mycophenolate mofetil or azathioprine.
Table 3 Areas of uncertainty in the prevention, diagnosis and management of new-onset diabetes after transplantation Prevention Intensive lifestyle intervention to prevent
NODAT Use of risk scores to focus intervention to
prevent NODAT Use of risk scores to guide immuno
Anti-hyperglycaemic therapy
Amelioration and possibly reversal of NODAT through intensive lifestyle interventions have already been reported but may not be sustainable [48]. Additionally, the onset of NODAT and Type 2 diabetes are not comparable; NODAT tends to have a more acute onset, requiring early drug therapy rather than relying on lifestyle interventions to reduce hyperglycaemia. International consensus guidelines recommend a stepwise approach similar to that taken in the treatment of Type 2 diabetes [4]. There is a lack of randomized clinical trials to assess the effectiveness and safety of oral anti-diabetic drugs in NODAT, and most of their use is based on guidelines of therapy in Type 2 diabetes. Although metformin is the drug of first choice for the pharmacological treatment of diabetes, low estimated GFR early in the post-transplant phase makes early use of metformin in NODAT difficult, although not impossible with careful monitoring. The safety and efficacy of repaglinide, a prandial glucose regulator, and rosiglitazone, a thiazolidenedione, have been reported in observational studies [55]. A small study of sitagliptin, a dipeptidylpeptidase-4 inhibitor, has shown safety and efficacy in 15 people post-transplant over 3 months [56]. A clinical trial to assess the efficacy and safety of vildagliptin in people with NODAT has been completed and results are awaited (the Vildagliptin in New Onset Diabetes After Transplantation study; Clinical Trials Registry no. NCT00980356) [57]. Although expert opinion does not recommended sulphonylureas for the treatment of NODAT, gliquidone use has been reported to be safe, efficacious and free of interactions with immunosuppressive agents [58]. It has been suggested that sulphonylureas may exacerbate declining b-cell function, a hallmark of NODAT, but they may still be useful in dealing with acute hyperglycaemia in the early post-transplant phase. Acute, severe hyperglycaemia in the post-transplant phase may most safely be managed with insulin therapy, although there are no data on the optimum regimen to use. Screening for diabetes-related complications
Once diagnosed, people with NODAT should be referred for ongoing screening for complications, including retinal screening, and screening for foot complications [4]. Urine testing for microalbuminuria has not been validated as a marker of nephropathy in people with NODAT, and indeed individuals may have microalbuminuria without diabetes as a result of renal insufficiency or chronic rejection [4].
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suppression regimen to prevent NODAT Use of drugs pre-transplant to prevent
NODAT Diagnosis Use of regular post-meal glucose/capillary
glucose to diagnose NODAT Use of HbA1c to diagnose NODAT
Management Use of change in immunosuppression
regimen in early NODAT Use of oral hypoglycaemic agents in early
NODAT Optimum insulin regimens in NODAT
NODAT, new-onset diabetes after transplantation.
Management of NODAT microvascular complications is similar to that for people with Type 2 diabetes. Multidisciplinary management
Renal transplant recipients require intensive management of nephrological and other indices in the early post-transplant period, and subsequent lifelong follow-up. The onset of NODAT in renal transplant recipients heralds an increased risk of complications, with renal and cardiovascular morbidity increasing significantly. The management of NODAT may, therefore, be undertaken usefully in a joint multidisciplinary setting, involving nephrologists, diabetologists and specialist nursing/dietetic teams, in order to provide seamless care. A combined clinic allows such patients to undergo careful nephrological management, plus management and monitoring of diabetes and screening for diabetes complications.
Conclusions New-onset diabetes after transplantation is an important comorbidity in renal transplant recipients. The condition is common, and likely to be caused by a number of pre- and post-transplant-related factors, including pre- and post-transplant therapy, and patient-related risk factors for metabolic problems. The onset of hyperglycaemia after renal transplant appears to lead to increased risks, and these need careful management
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Review article
and monitoring to ensure renal and other complications do not ensue. The diagnosis, management and monitoring of people with NODAT is hampered by a lack of available clinical evidence, and whilst NODAT appears to be an important clinical entity, there are significant gaps in our knowledge of the condition. Some areas of uncertainty that need further research are listed in Table 3.
Funding sources
None.
Competing Interests
None declared.
References 1 Diabetes UK. Diabetes in the UK in 2010: Key Statistics on Diabetes 2011. Available at: http://www.diabetes.org.uk/Documents/Reports/ Diabetes_in_the_UK_2010.pdf. Last accessed 11 April 2014. 2 The Renal Association. UK Renal Registry 2009. Nephron Clin Pract 2010;115 (Suppl.1): c1–c370. 3 Starzl TE, Marchioro TL, Rifkind D, Holmes JH, Rowlands DT, Waddell WR. Factors in Successful Renal Transplantation. Surgery 1964; 56: 296–318. 4 Wilkinson A, Davidson J, Dotta F, Home PD, Keown P, Kiberd B et al. Guidelines for the treatment and management of new-onset diabetes after transplantation. Clin Transplant 2005; 19: 291– 298. 5 World Health Organisation, 2011. Use of glycated haemoglobin (HbA1c) in the diagnosis of diabetes mellitus. Abbreviated report of a WHO consultation. WHO Geneva. Available at: http://www.who. int/diabetes/publications/report-hba1c_2011.pdf. Last accessed 11 April 2014. 6 Valderhaug TG, Jenssen T, Hartmann A, Midtvedt K, Holdaas H, Reisaeter AV et al. Fasting plasma glucose and glycosylated hemoglobin in the screening for diabetes mellitus after renal transplantation. Transplantation 2009; 88: 429–434. 7 Shabir S, Jham S, Harper L, Ball S, Borrows R, Sharif A. Validity of glycated haemoglobin to diagnose new onset diabetes after transplantation. Transpl Int 2013; 26: 315–321. 8 Pham PT, Edling KL, Chakkera HA, Pham PC, Pham PM. Screening strategies and predictive diagnostic tools for the development of new-onset diabetes mellitus after transplantation: an overview. Diabetes Metab Syndr Obes 2012; 5: 379–387. 9 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– 1672. 10 Cosio FG, Kudva Y, van der Velde M, Larson TS, Textor SC, Griffin MD et al. New onset hyperglycemia and diabetes are associated with increased cardiovascular risk after kidney transplantation. Kidney Int 2005; 67: 2415–2421. 11 Yates CJ, Fourlanos S, Colman PG, Cohney SJ. Screening for new-onset diabetes after kidney transplantation: limitations of fasting glucose and advantages of afternoon glucose and glycated hemoglobin. Transplantation 2013; 96: 726–731. 12 Bergrem HA, Valderhaug TG, Hartmann A, Hjelmesaeth J, Leivestad T, Bergrem H et al. Undiagnosed diabetes in kidney transplant candidates: a case-finding strategy. Clin J Am Soc Nephrol 2010; 5: 616–622.
ª 2014 The Authors. Diabetic Medicine ª 2014 Diabetes UK
DIABETICMedicine
13 Kasiske BL, Snyder JJ, Gilbertson D, Matas AJ. Diabetes mellitus after kidney transplantation in the United States. Am J Transplant 2003; 3: 178–185. 14 Chakkera HA, Knowler WC, Devarapalli Y, Weil EJ, Heilman RL, Dueck A et al. Relationship between inpatient hyperglycemia and insulin treatment after kidney transplantation and future new onset diabetes mellitus. Clin J Am Soc Nephrol 2010; 5: 1669– 1675. 15 Woodward RS et al. Incidence and cost of new onset diabetes mellitus among U.S. wait-listed and transplanted renal allograft recipients. Am J Transplant 2003; 3: 590–598. 16 First MR, Dhadda S, Croy R, Holman J, Fitzsimmons WE. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation 2013; 96: 58–64. 17 Chakkera HA, Weil EJ, Pham PT, Pomeroy J, Knowler WC. Can new-onset diabetes after kidney transplant be prevented? Diabetes Care 2013; 36: 1406–1412. 18 Zelle DM, Corpeleijn E, Deinum J, Stolk RP, Gans RO, Navis G et al. Pancreatic beta-cell dysfunction and risk of new-onset diabetes after kidney transplantation. Diabetes Care 2013; 36: 1926–1932. 19 Hecking M, Haidinger M, D€ oller D, Werzowa J, Tura A, Zhang J, Tekoglu H et al. Early basal insulin therapy decreases new-onset diabetes after renal transplantation. J Am Soc Nephrol 2012; 23: 739–749. 20 Bayes B, Granada ML, Pastor MC, Lauzurica R, Salinas I, Sanmartı A et al. Obesity, adiponectin and inflammation as predictors of new-onset diabetes mellitus after kidney transplantation. Am J Transplant 2007; 7: 416–422. 21 Hjelmesaeth J, Hartmann A, Kofstad J, Stenstrøm J, Leivestad T, Egeland T et al. Glucose intolerance after renal transplantation depends upon prednisolone dose and recipient age. Transplantation 1997; 64: 979–983. 22 Woodle ES, First MR, Pirsch J, Shihab F, Gaber AO, Van Veldhuisen P et al. A prospective, randomized, double-blind, placebo-controlled multicenter trial comparing early (7 day) corticosteroid cessation versus long-term, low-dose corticosteroid therapy. Ann Surg 2008; 248: 564–577. 23 Webster A, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus cyclosporin as primary immunosuppression for kidney transplant recipients. Cochrane Database Syst Rev 2005: CD003961. 24 Busque S, Cantarovich M, Mulgaonkar S, Gaston R, Gaber AO, Mayo PR, Ling S et al. The PROMISE study: a phase 2b multicenter study of voclosporin (ISA247) versus tacrolimus in de novo kidney transplantation. Am J Transplant 2011; 11: 2675– 2684. 25 Johnston O, Rose CL, Webster AC, Gill JS. Sirolimus is associated with new-onset diabetes in kidney transplant recipients. J Am Soc Nephrol 2008; 19: 1411–1418. 26 Montori VM, Basu A, Erwin PJ, Velosa JA, Gabriel SE, Kudva YC. Posttransplantation diabetes: a systematic review of the literature. Diabetes Care 2002; 25: 583–592. 27 Prasad N, Gurjer D, Bhadauria D, Gupta A, Srivastava A, Kaul A et al. Is basiliximab induction, a novel risk factor for new onset diabetes after transplantation for living donor renal allograft recipients? Nephrology (Carlton) 2014; 19: 244–250. 28 Vanrenterghem Y, Bresnahan B, Campistol J, Durrbach A, Griny o J, Neumayer HH et al. Belatacept-based regimens are associated with improved cardiovascular and metabolic risk factors compared with cyclosporine in kidney transplant recipients (BENEFIT and BENEFIT-EXT studies). Transplantation. 2011; 91: 976–983. 29 Kim YG, Ihm CG, Lee TW, Lee SH, Jeong KH, Moon JY, Chung JH et al. Association of genetic polymorphisms of interleukins with new-onset diabetes after transplantation in renal transplantation. Transplantation 2012; 93: 900–907.
1291
DIABETICMedicine
New-onset diabetes after renal transplantation N. Tufton et al.
30 Hamer RA, Chow CL, Ong AC, McKane WS. Polycystic kidney disease is a risk factor for new-onset diabetes after transplantation. Transplantation 2007; 83: 36–40. 31 Bayer ND, Cochetti PT, Anil Kumar MS, Teal V, Huan Y, Doria C et al. Association of metabolic syndrome with development of new-onset diabetes after transplantation. Transplantation 2010; 90: 861–866. 32 Kuypers DR, Claes K, Bammens B, Evenepoel P, Vanrenterghem Y. Early clinical assessment of glucose metabolism in renal allograft recipients: diagnosis and prediction of post-transplant diabetes mellitus (PTDM). Nephrol Dial Transplant 2008; 23: 2033–2042. 33 Chakkera HA, Weil EJ, Swanson CM, Dueck AC, Heilman RL, Reddy KS et al. Pretransplant risk score for new-onset diabetes after kidney transplantation. Diabetes Care 2011; 34: 2141–2145. 34 Rodrigo E, Santos L, Pi~ nera C, Millan JC, Quintela ME, Toyos C et al. Prediction at first year of incident new-onset diabetes after kidney transplantation by risk prediction models. Diabetes Care 2012; 35: 471–473. 35 Israni AK, Snyder JJ, Skeans MA, Kasiske BL. PORT Investigators. Clinical diagnosis of metabolic syndrome: predicting new-onset diabetes, coronary heart disease, and allograft failure late after kidney transplant. Transpl Int 2012; 25: 748–757. 36 Sharif A, Baboolal K. Complications associated with new-onset diabetes after kidney transplantation. Nat Rev Nephrol 2012; 8: 34–42. 37 Miles AM, Sumrani N, Horowitz R, Homel P, Maursky V, Markell MS et al. Diabetes mellitus after renal transplantation: as deleterious as non-transplant-associated diabetes? Transplantation 1998; 65: 380–384. 38 Matas AJ, Gillingham KJ, Humar A, Ibrahim HN, Payne WD, Gruessner RW et al. Post-transplant diabetes mellitus and acute rejection: impact on kidney transplant outcome. Transplantation 2008; 85: 338–343. 39 Tsai JP, Lian JD, Wu SW, Hung TW, Tsai HC, Chang HR. Long-term impact of pretransplant and post-transplant diabetes mellitus on kidney transplant outcomes. World J Surg 2011; 35: 2818–2125. 40 Siraj ES, Abacan C, Chinnappa P, Wojtowicz J, Braun W. Risk factors and outcomes associated with post-transplant diabetes mellitus in kidney transplant recipients. Transplant Proc 2010; 42: 1685–1689. 41 Revanur VK, Jardine AG, Kingsmore DB, Jaques BC, Hamilton DH, Jindal RM. Influence of diabetes mellitus on patient and graft survival in recipients of kidney transplantation. Clin Transplant 2001; 15: 89–94. 42 Kuo HT, Sampaio MS, Vincenti F, Bunnapradist S. Associations of pretransplant diabetes mellitus, new-onset diabetes after transplant, and acute rejection with transplant outcomes: an analysis of the Organ Procurement and Transplant Network/United Network for Organ Sharing (OPTN/UNOS) database. Am J Kidney Dis 2010; 56: 1127–1139. 43 Joss N, Staatz CE, Thomson AH, Jardine AG. Predictors of new onset diabetes after renal transplantation. Clin Transplant 2007; 21: 136–143. 44 Cotovio P, Neves M, Rodrigues L, Alves R, Bastos M, Baptista C et al. New-onset diabetes after transplantation: assessment of risk factors and clinical outcomes. Transplant Proc 2013; 45: 1079–1083.
45 Israni AK, Snyder JJ, Skeans MA, Peng Y, Maclean JR, Weinhandl ED et al. Predicting coronary heart disease after kidney transplantation: Patient Outcomes in Renal Transplantation (PORT) Study. Am J Transplant 2010; 10: 338–353. 46 Leavey SF, McCullough K, Hecking E, Goodkin D, Port FK, Young EW. Body mass index and mortality in ‘healthier’ as compared with ‘sicker’ haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2001; 16: 2386–2394. 47 Painter P, Ward K, Nelson RD. Self-reported physical activity in patients with end stage renal disease. Nephrol Nurs J 2011; 38: 139–147. 48 Sharif A, Moore R, Baboolal K. Influence of lifestyle modification in renal transplant recipients with postprandial hyperglycemia. Transplantation 2008; 85: 353–358. 49 Kamar N, Toupance O, Buchler M, Sandres-Saune K, Izopet J, Durand D et al. Evidence that clearance of hepatitis C virus RNA after alpha-interferon therapy in dialysis patients is sustained after renal transplantation. J Am Soc Nephrol 2003; 14: 2092–2098. 50 Prasad GVR, Kim SJ, Huang M, Nash MM, Zaltzman JS, Fenton SS et al. Reduced Incidence of New-Onset Diabetes Mellitus after Renal Transplantation with 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Inhibitors (Statins). Am J Transplant 2004; 4: 1897–1903. 51 Werzowa J, Hecking M, Haidinger M, Lechner F, D€ oller D, Pacini G et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation: a randomized, placebo-controlled clinical trial. Transplantation 2013; 95: 456– 462. 52 Oberholzer J, Thielke J, Hatipoglu B, Testa G, Sankary HN, Benedetti E. Immediate conversion from tacrolimus to cyclosporine in the treatment of posttransplantation diabetes mellitus. Transplant Proc 2005; 37: 999–1000. 53 Teutonico A, Schena PF, Di Paolo S. Glucose metabolism in renal transplant recipients: effect of calcineurin inhibitor withdrawal and conversion to sirolimus. J Am Soc Nephrol 2005; 16: 3128– 3135. 54 Madsen JC. KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients. Am J Trans 2009; 9: S1–S155. 55 Turk T, Pietruck F, Dolff S, Kribben A, Janssen OE, Mann K et al. Repaglinide in the management of new-onset diabetes mellitus after renal transplantation. Am J Transplant 2006; 6: 842–846. 56 Lane JT, Odegaard DE, Haire CE, Collier DS, Wrenshall LE, Stevens RB et al. Sitagliptin therapy in kidney transplant recipients with new-onset diabetes after transplantation. Transplantation 2011; 92: e56–57. 57 Haidinger M, Werzowa J, Voigt HC, Pleiner J, Stemer G, Hecking M et al. A randomized, placebo-controlled, double-blind, prospective trial to evaluate the effect of vildagliptin in new-onset diabetes mellitus after kidney transplantation. Trials 2010; 11: 91. 58 Ghisdal L, Van Laecke S, Abramowicz MJ, Vanholder R, Abramowicz D. New-Onset Diabetes After Renal Transplantation: Risk assessment and management. Diabetes Care 2012; 35: 181– 188.
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