Fig. 21.1
Components of TAH
Diagnostic Considerations
While both the World Health Organization and ADA definitions are accepted, we prefer the ADA based on a slightly higher level of stringency regarding IFG (Table 21.1). Utilizing this classification to its maximal extent requires the use of oral glucose tolerance testing (OGTT) which should ideally include both pre- and post-transplant testing. In the early post-transplant period, interpretation of this test may be confounded by hyperglycemia persisting up to 9 h after administration of high-dose steroids [2]. Yates and colleagues have recently proposed the use of hemoglobin A1C (HgbA1C) as an alternative diagnostic test since it can be measured in a non-fasting state, reflects average blood glucose levels over 2–3 months, and correlates well with development of microvascular complications in non-transplant diabetes [3].
Table 21.1
American Diabetes Association classification of diabetes mellitus
Criteria | Normal (mg/dL) | IGT/IFG (mg/dL) | Diabetes (mg/dL) |
|---|---|---|---|
Random plasma glucose with symptoms (polyuria, polydipsia, weight loss) | ≥200 | ||
Fasting plasma glucose | <100 | 100–125 | ≥126 |
2-h Oral GTT | <140 | 140–199 | ≥200 |
While HgbA1C is more biologically stable and has less variability than plasma glucose, it may not be universally available and levels may be affected by the effects of uremia, blood transfusions, erythrocyte-stimulating agent administration, and hemolysis, all factors frequently observed in the perioperative period until the hematocrit stabilizes. A Norwegian study of 929 kidney recipients with nondiabetic FBG at 10 weeks post-transplant found that the combined criterion of fasting blood glucose >90 mg/dL and HgbA1C ≥5.7 % provided a sensitivity of 79 %, from testing only 29 % of the post-transplant population [4]. The KDIGO Guidelines recommend diabetes screening intervals after transplantation as follows: weekly for first 4 weeks; months 3, 6, and 12; and annually after the first year [1].
Incidence and Prevalence
Estimation of the cumulative incidence of TAH depends on the population studied and the surveillance method used. The US registry data analysis suggests that 15 % of kidney recipients develop clinically diagnosed NODAT by 1 year after transplantation that increases to around 25 % by the end of the third post-transplant year [5]. Single-center reports that have utilized OGTT routinely before and after transplantation indicate that approximately 8 % of patients on the kidney waiting list had undiagnosed diabetes, while at least another one-third had either undiagnosed IFG or IGT [6]. After transplant, in addition to kidney recipients classified as having NODAT, the prediabetic states are present in 30–45 % of kidney recipients by 1 year [7]. Sharif and colleagues reported that among 122 patients with fasting plasma glucose 93–125 mg/dL tested by OGTT a median of 5 years post-transplant, over 50 % of patients had TAH, with 10 % meeting criteria for overt NODAT [8]. Evidence from both a meta-analysis and prospective clinical trials confirms that TAH occurs in a substantial proportion of transplant recipients and should be a major cause for concern [9–11].
Transient Versus Persistent TAH
Although reported surprisingly infrequently, transient NODAT in the perioperative phase is a well-recognized post-transplant complication [12]. Accounting for about one-third of NODAT, the transient form is commonly attributed to high steroid dosing and tends to reverse as the glucocorticoid dose diminishes. In a study by Kiberd and colleagues, most transient NODAT developed within the first post-transplant month and had resolved by 12 months after transplant [12]. Most studies suggest that transient NODAT is associated with similar outcomes to nondiabetic recipients unlike in patients that have persistent NODAT where there is an increased risk of cardiovascular adverse events.
Impact of TAH on Outcomes
NODAT is associated with an elevated risk for death, similar to that seen in patients in the general population afflicted with diabetes [5]. Part of the excess mortality in recipients with NODAT may be attributed to infectious complication; however, several studies have now linked NODAT to increased cardiovascular risk as well [5, 13, 14]. Post-transplant follow-up in these studies ranged between 3 and 5 years. Although atherogenesis attributable to hyperglycemia would be expected to develop over a much longer time frame, these previously nondiabetic CKD patients have had a significant cardiovascular risk factor burden for many years.
Hyperglycemia may therefore alter the quantity or quality of established atherosclerosis over a short time frame to promote vascular events. However, it is possible that hyperglycemia per se is not directly responsible for increased cardiovascular disease in patients with NODAT. Rather, NODAT may represent a surrogate of systemic inflammation occurring in a dysregulated post-transplant metabolic milieu characterized not just by abnormal glucose homeostasis but also by deterioration in the lipid profile, higher BP, and elevated inflammatory markers. Even after multivariable adjustment for these other factors, however, Ducloux and co-investigators demonstrated that TAH remains an independent risk factor for cardiovascular events [14]. In a single-center study with similarly detailed information about the metabolic profile of kidney transplant recipients, Cosio et al. reported an adjusted hazard ratio for mortality of 1.80 (P < 0.01) associated with NODAT [15].
A recent prospective observational study in 1,410 patients investigated the predictive value of a 10-week post-transplant OGTT on the outcomes of kidney recipients with TAH [16]. With a median 6.7 years of follow-up, NODAT was associated with a 1.8-fold increase in cardiovascular mortality and a 1.5-fold increase in overall mortality. Considering the prediabetic states only, IFG was not linked to mortality, while IGT was associated with a 1.4-fold increased death risk, attributable to infection rather than cardiovascular mortality. The increasingly recognized negative impact of NODAT on graft survival is further fuelled in a US registry data study that suggested that for many patients with this complication, mortality becomes an important competing outcome, to the extent that TAH makes it more likely that a patient will die before the allograft fails [17].
Besides the adverse influence of TAH on clinical outcomes, it is widely appreciated that glucose dysregulation after transplant carries with it a substantial economic burden as well. Woodward et al. examined the United States Renal Data System’s records for kidney recipients transplanted between 1996 and 1997 and found that by 2 years post-transplant there was an additional $21,500 of cost associated with each patient with NODAT [18]. Because this study relied on Medicare claims data to ascertain a diagnosis of NODAT, it is likely that there was bias towards the affected population having more complicated disease. Therefore, patients with milder forms of NODAT or transient NODAT requiring less intensive treatment may not have been included in the analysis, thereby potentially overestimating the true cost per affected patient.
However, since the publication of this above economic analysis, it is plausible that the effect of recent guidelines and adoption of more stringent diagnostic criteria for TAH may have resulted in greater attention being paid to blood glucose measurement in the perioperative period, thereby leading to fewer readmissions for poorly controlled hyperglycemia. However, it remains to be determined whether this is indeed the case and if so, whether any realized cost saving has been offset by greater expense associated with increased vigilance in glucose management, e.g., use of glucose-lowering therapies, glucose monitoring devices, diabetologist consultation, and education.
The Metabolic Syndrome and Transplant-Associated Hyperglycemia
The metabolic syndrome comprises a constellation of modifiable cardiovascular risk factors that cluster together sharing systemic insulin resistance as a root cause. Metabolic syndrome predisposes to systemic inflammation and cardiovascular disease, while its components (hyperglycemia, hypertension, dyslipidemia, central obesity) are risk factors for progressive kidney disease. Following kidney transplantation, the prevalence of metabolic syndrome increases in conjunction with weight gain [19]. A single-center investigation has shown that, together with obesity, metabolic syndrome is associated with NODAT, as well as inferior patient and graft outcomes [20]. More recently, the multicenter, multinational prospective observational Patient Outcomes in Renal Transplantation (PORT) study comprising 2,253 patients extended these earlier single-center findings by demonstrating that metabolic syndrome was independently associated with subsequent risk of NODAT (hazard ratio 3.46, 95 % CI (2.40–4.98), p < 0.001) [21]. Examining data from another multicenter observational cohort, Rosas et al. reported that by 1 year post-transplant, there was an incremental growth in the prevalence of NODAT as the number of metabolic syndrome components increased (prevalence at 1 year: 1 component: 24.2 %, 2 components: 29.3 %, 3 components: 31 %, 4 components: 34.8 %, 5 components; P = 0.01) [22]. We therefore recommend that screening for diabetes and the metabolic syndrome be conducted in concert. It follows that identification, and treatment, of metabolic syndrome in transplant recipients is central to optimizing post-transplant care. While intervention to correct individual components of the metabolic syndrome will be beneficial, recognition of the central pathogenic role of insulin resistance should guide aggressive lifestyle intervention and stimulate clinical investigation of pharmacologic efforts to promote insulin sensitivity and weight loss in the transplant population.
Pathogenesis and Risk Factors
Although the pathogenesis of TAH has similarities with development of hyperglycemia in the general population, kidney recipients have additional distinct pathophysiological mechanisms related to the concomitant generic and transplant-specific risk factors. Glycemic homeostasis is reached by achieving equilibrium between insulin production and bodily needs of insulin. Imbalances arise when pancreatic beta-islet cell insulin production decreases, and insulin need increases or in states of insulin resistance. An extensive literature on TAH has illuminated the many risk factors for development of TAH.
Preexisting risks that predispose individuals to NODAT include increasing age, obesity, male gender, non-Caucasian race, and a family history of diabetes. These traditionally non-modifiable characteristics reflect inherited and acquired defects in insulin sensitivity and β-cell function that contribute to glucose dysregulation. The high incidence of TAH in the months following transplantation reflects superimposition of new, transplant-specific factors on the baseline metabolic milieu of predisposed individuals. The best-elucidated transplant-specific exposures include immunosuppressive agents such as glucocorticoids, calcineurin inhibitors (CNIs) and sirolimus, post-transplant weight gain, and hepatitis C virus (HCV) infection.
Immunosuppression and Transplant-Associated Hyperglycemia
Glucocorticoids
Glucocorticoids impact glucose metabolism by enhancing glucose production in the liver and by reducing peripheral tissue insulin sensitivity. Prior to the introduction of CNIs into the clinical arena, heavy reliance on corticosteroid-based immunosuppression resulted in high rates of NODAT. The supraphysiologic glucocorticoid doses used in early post-transplant induction regimens strongly contribute to very early post-transplant hyperglycemia that may normalize thereafter once steroids are either withdrawn or tapered into the physiologic range.
Calcineurin Inhibitors
The CNIs, tacrolimus and cyclosporine, are strongly associated with development of TAH. Mechanistic clinical and basic science studies demonstrate the critical role of calcineurin in β-cell growth and function. CNIs impair β-cell function by diminishing insulin gene expression, thereby predisposing to TAH [23]. CNIs, especially tacrolimus in the contemporary era, form the foundation of most maintenance immunosuppressive regimens. Most efficacy studies comparing cyclosporine and tacrolimus in kidney recipients have demonstrated higher TAH risk with the latter therapy. The DIRECT trial, a randomized, prospective, multicenter study that compared cyclosporine to tacrolimus, was unique in that the composite of NODAT and IFG within the first six post-transplant months was the primary safety endpoint analyzed [10]. Through the use of sequential OGTT, the study demonstrated rates of abnormal glucose homeostasis of 26 and 33.6 % in cyclosporine- and tacrolimus-treated patients, respectively, with no efficacy difference between the two drugs. NODAT was more frequently transient among cyclosporine- than tacrolimus-treated recipients. The lack of standardization of steroid dosage, open-label design, and enrolment predominantly of Caucasian patients limits generalizability of this study to other populations from either an efficacy or adverse events standpoint. Early clinical studies have more recently indicated that voclosporin, an emerging CNI still in development, has similar efficacy to tacrolimus, but is less diabetogenic [24]. Regardless, studies confirm that CNIs promote TAH and implicate impaired insulin secretion as the etiology.
Target of Rapamycin Inhibitors
The target of rapamycin (TOR) inhibitors, sirolimus and everolimus, inhibit the mammalian target of rapamycin, a widely expressed cellular kinase that mediates cytokine-induced lymphocyte proliferation. Sirolimus, for which there is far more clinical experience, impairs insulin-mediated suppression of hepatic glucose production, causes insulin resistance as a result of ectopic triglyceride deposition, and may exhibit direct β-cell toxicity [25, 26]. In clinical studies, sirolimus in combination with CNI has been associated with higher rates of diabetes than with the CNI alone and use of sirolimus in CNI-elimination regimens has resulted in diminished insulin sensitivity and increased insulin resistance [27, 28]. A recent safety analysis from a randomized controlled trial with everolimus and cyclosporine combination therapy demonstrated a direct relationship between rates of NODAT and increasing everolimus trough concentrations. Thus, although TOR inhibitors are potential therapeutic alternatives to CNIs, their use is unlikely to diminish the incidence of TAH.
Other Immunosuppressive Agents
Other than as isolated reports, the remaining immunosuppressive agents typically used in transplantation have not been associated with NODAT. This includes the antiproliferative agents, mycophenolate mofetil, mycophenolic acid and azathioprine, as well as belatacept.
Obesity
Almost two-thirds of kidney transplant candidates are overweight or obese at the time of transplantation. Shah and colleagues followed patients followed over a mean of 306 days post-transplant and found that the risk of NODAT increased 1.5-fold for overweight and almost twofold for obese individuals [29]. As the optimal criteria for characterizing obesity risk evolve, there is increasing recognition in the general population of the stronger relationship between central obesity, reflected by waist circumference and waist/hip ratio, and cardiovascular disease, rather than traditional BMI measures. To date, one prospective study has extended this observation to kidney transplant recipients as well, where waist circumference was directly related to, while BMI had an inverse association with, all-cause mortality [30].
HCV Infection
Epidemiological studies have strongly associated HCV infection and hyperglycemia in the general population though the pathogenic mechanisms remain to be completely elucidated. Potential mechanisms include increased insulin resistance due to a post-receptor signaling defect induced by HCV infection, diminished hepatic glucose uptake and glycogenesis, as well as a direct cytopathic effect of the virus on β-cells in the pancreas. Growing evidence suggests that a predominant effect of the virus is the induction of insulin resistance and reduced insulin sensitivity, an effect that has been demonstrated in HCV-infected clinically stable kidney transplant recipients [31].
It is likely through this mechanism that HCV infection has also been linked to NODAT in kidney recipients. In one registry study, HCV infection was associated with a 33 % increase in the risk of NODAT [5], while another single-center investigation indicated that the NODAT rate was 40 % among HCV-infected recipients compared to 10 % in uninfected patients [32]. Most of this effect was due to an elevated risk of NODAT among HCV-infected patients treated with tacrolimus. Whether this propensity to NODAT represents exposure to concomitant diabetogenic insults of HCV and tacrolimus versus a more permissive effect of tacrolimus on HCV replication is presently unknown. Taken together, these studies demonstrate that HCV infection predisposes patients to NODAT and that the choice of CNI may have important modifying effects on that risk. Since viral clearance may improve glucose tolerance [33], HCV infection may represent a modifiable risk factor for TAH.
Restoration of Renal Insulin Metabolism
Increased insulin metabolism that occurs concomitantly with restoration of kidney function is an uncommonly cited, but potentially important contributor to TAH. Healthy kidneys contribute significantly to insulin degradation, an effect that is underscored by the marked renal arteriovenous decrease in insulin concentration and the decreased insulin requirements observed clinically as kidney disease progresses in patients with diabetes. Therefore, a functioning kidney transplant unmasks restored insulin metabolism representing is an important, non-modifiable factor that increases post-transplant insulin requirements.
Genetic Polymorphism
Multiple studies have demonstrated that genetic polymorphisms may predispose to diabetes by likely mechanism of apoptosis and beta-cell dysfunction, a key perturbation involved in NODAT pathogenesis. Using a cohort of 306 kidney transplant recipients with no known diabetes mellitus prior to transplant, Kim et al. analyzed a panel of 18 single nucleotide peptides (SNP) within ten genes of the interleukins or their receptors; 53 patients developed NODAT and 11 SNPs were significantly associated with NODAT (IL-7R, IL-17E, IL-17R, and IL-17RB) [34]. Other identified gene polymorphisms associated with NODAT include KNNJ11, a gene leading to impaired β-cell insulin release, and NFATc4.
Other studies have also reported an association between NODAT and specific genes (transcription factor 7-like 2 (TCF7L2), member 8 genes, chemokine ligand 5 gene (CCL5), and vitamin D receptor, KNNJ11).
Further investigations that corroborate and then expand these findings are needed before this technology can be widely utilized in clinical practice. The potential to identify at-risk patients beforehand in order to provide necessary lifestyle modification counseling and to tailor immunosuppression to reduce the risk of NODAT would represent an appealing and substantive advancement to the field.
Detection and Management of NODAT
Detecting and adjusting modifiable risk factors to prevent or minimize the development of TAH is a desirable objective in this patient population. Efforts to accomplish this goal should be initiated in the pre-transplant phase and continue through the early and later post-transplant phases.
Pre-transplant
Identifying at-risk patients in the pre-transplant period may provide the opportunity to actively encourage patient-centered interventions that mitigate later NODAT risk and to facilitate the development of less-diabetogenic immunosuppressive regimens. During this phase, management should focus on risk factor screening (especially for metabolic syndrome and cardiovascular disease), establishing baseline glycemic regulation by checking FPG and 2-h OGTT, counseling and lifestyle modification as well as dietitian referrals as needed. A potential role for bariatric surgery in this setting has not been formally evaluated; however, besides the need to ascertain effectiveness of this treatment for preventing or treating diabetes in this population, an examination of the impact of this surgery on immunosuppressive drug pharmacokinetics and efficacy would be imperative.
For HCV-infected kidney transplant candidates, the induction of a sustained virologic response before transplant is highly desirable. Although interferon may improve glucose tolerance in HCV-infected patients without kidney disease [33], the use of this antiviral therapy is contraindicated after kidney transplantation because of unacceptable rejection risk. However, preliminary evidence suggests that induction of a pre-transplant sustained virologic response by treatment with interferon usually persists after transplantation and may be associated with a reduced incidence of NODAT [35, 36]. Whether the emergence of the new classes of antiviral therapies will supersede the need for pre-transplant interferon remains to be determined.
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