Version July 2025
INTRODUCTION —
Diabetes is a common complication following kidney transplantation. Posttransplantation diabetes mellitus (PTDM) is associated with increased mortality and morbidity and, in particular, higher rates of cardiovascular disease and infection, which are the leading causes of death in kidney transplant recipients.
This topic reviews the epidemiology, risk factors, and clinical implications of PTDM, as well as recommendations for evaluation and treatment. Issues relating to kidney transplantation and combined kidney-pancreas transplantation in patients with preexisting diabetes are discussed elsewhere:
●(See "Kidney transplantation in diabetic kidney disease".)
●(See "Pancreas-kidney transplantation in diabetes mellitus: Benefits and complications".)
TERMINOLOGY
●Transient posttransplant hyperglycemia – This term refers to transient hyperglycemia that occurs in the immediate-to-early posttransplant setting, generally as a result of postsurgical stress or with the peri-operative and subsequent administration of high-dose glucocorticoids [1]. In most cases, posttransplant hyperglycemia resolves within the first few weeks after transplantation. Transient hyperglycemia may also occur later posttransplant in the setting of acute infection or treatment of rejection. Such patients should not be diagnosed with diabetes.
●New-onset diabetes mellitus after transplantation (NODAT) – This term was established by an international consensus guideline in 2003 to describe the pathophysiological effects of transplantation on glucose metabolism [2]. The term NODAT solely applies to onset of diabetes after transplant and excludes patients who may have had unrecognized diabetes prior to transplant.
●Posttransplantation diabetes mellitus (PTDM) – PTDM describes the diagnosis of diabetes after transplantation, irrespective of whether it may have been present but undetected before transplantation. We and others [3] prefer this term over NODAT because many transplant centers do not screen for diabetes during the pretransplant evaluation, so pretransplant diabetes is often not accurately identified. PTDM excludes patients with transient posttransplant hyperglycemia and requires both of the following:
•Hyperglycemia must persist at least six weeks after transplant and
•Hyperglycemia must meet American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus (table 1) [4].
However, when possible, we prefer to differentiate between diabetes that was undiagnosed during the pretransplant period (typically type 2 diabetes) and diabetes that develops in the posttransplant period, given the differences in the pathophysiology of these conditions [5-8]. Further, in contrast to type 2 diabetes, PTDM may resolve with time, early initiation of glucose-lowering pharmacotherapy and/or downward titration of immunosuppressive therapy.
●Other terms – Older terms, including posttransplantation hyperglycemia and diabetes after transplantation [5,9] are generally no longer used.
EPIDEMIOLOGY
Incidence — The reported incidence of posttransplantation diabetes mellitus (PTDM) is highly variable, in part reflecting differences in the definitions used, time from transplant, study populations, and immunosuppressive agents used for individual studies. Overall, studies that use the existing criteria for diagnosis suggest that approximately 15 to 20 percent of kidney transplant recipients without a prior history of diabetes develop PTDM by six months posttransplantation [10-13], and approximately 20 to 30 percent develop PTDM over long-term follow-up [14-18].
Risk factors — Risk factors for PTDM include the following:
●Pretransplant risk factors – Certain factors present before transplantation may predispose patients to insulin resistance and/or pancreatic beta cell dysfunction.
Potentially modifiable risk factors include the following:
•Obesity – Several studies have found an association between obesity (body mass index of ≥30 kg/m2) and increased risk of PTDM [19-27].
•Hepatitis C infection – Hepatitis C virus (HCV) infection correlates with both pre- and posttransplant diabetes [19,23,24,28-32]. A meta-analysis of 10 studies involving 2502 kidney transplant recipients found that HCV-positive patients, compared with uninfected individuals, were nearly four times more likely to have PTDM [31]. Proposed mechanisms for HCV-induced PTDM include HCV-induced islet cell dysfunction and insulin resistance due to liver dysfunction [33]. HCV infection is a potentially modifiable risk factor for PTDM as treatment prior to transplantation may decrease the incidence of PTDM [34].
Cytomegalovirus (CMV) infection has also been reported to increase the risk of PTDM [35,36].
Nonmodifiable risk factors include the following [2,19,20,23,27,37-40]:
•Increased age (≥40 to 45 years)
•History of gestational diabetes or first-degree relative with type 2 diabetes
•Genetic factors – Genetic factors may also contribute to the risk of developing PTDM after kidney transplantation [41-44]. However, findings have been inconclusive and differ among studied populations. Identifying genetic risk factors for PTDM eventually may inform the choice of immunosuppressive therapy. However, data are insufficient to guide such management decisions, and routine genetic testing is not recommended.
●Posttransplant risk factors – The most important posttransplant risk factor for PTDM is immunosuppressive therapy, which can contribute to both reduced insulin secretion and increased insulin resistance.
•Immunosuppressive agents – Immunosuppressive agents that contribute to PTDM include glucocorticoids, calcineurin inhibitors (CNIs), and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors.
-Glucocorticoids – Higher doses of glucocorticoids particularly raise postprandial glucose levels and have been associated with the development of PTDM [39,45-48]. In one study of 173 patients, for example, the risk of developing PTDM was 5 percent per 0.01 mg/kg per day increase in prednisolone dose. Increased use of glucocorticoid-sparing immunosuppressive regimens may explain the significant decrease in rates of PTDM compared with those reported several decades ago (eg, 46 percent in 1979) [39,45-48].
However, complete glucocorticoid withdrawal has not been clearly shown to reduce the incidence of PTDM [49-52]. Moreover, acute rejection can follow glucocorticoid withdrawal and requires reinstitution of glucocorticoid therapy, often with high doses. Pulsed, high-dose glucocorticoid therapy for acute rejection increases the risk for PTDM [53]. Thus, the metabolic benefits of glucocorticoid withdrawal must be weighed against the risk of allograft rejection. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Glucocorticoids'.)
-CNIs – Both cyclosporine and tacrolimus increase the risk of PTDM [25]. Tacrolimus is more diabetogenic than cyclosporine [17,19,23,24,28,54-61], and higher tacrolimus levels may predict dysglycemia. In one study, levels >15 ng/mL were associated with the development of glucose intolerance and PTDM at one year posttransplant [22]. Incidence rates of PTDM appear similar with extended-release versus immediate-release tacrolimus formulations [62].
Both CNIs cause reversible toxicity to islet cells and may directly affect transcriptional regulation of insulin expression [63,64]. Some evidence suggests tacrolimus causes more severe swelling and vacuolization of islet cells [65].
-mTOR inhibitors – Sirolimus is diabetogenic [55,66], and switching from tacrolimus or cyclosporine to sirolimus has been associated with significant worsening of insulin resistance. The incidence of PTDM appears to be similar between a sirolimus- and everolimus-based regimen and between early and late conversion from a CNI to an mTOR inhibitor [67].
-Other agents – Azathioprine, mycophenolate mofetil (MMF), and belatacept do not have independent diabetogenic effects. In one large, retrospective study, the use of azathioprine and MMF was associated with a decreased risk of PTDM (relative risk [RR] 0.84, 95% CI 0.72-0.97 and 0.78, 95% CI 0.69-0.88, respectively) [19]. This benefit may be explained by the use of lower doses of glucocorticoids with these drugs, although this is unproven.
•Perioperative hyperglycemia – Perioperative hyperglycemia is associated with the development of PTDM [55,68]. In one retrospective study, among 349 patients who developed hyperglycemia during the transplantation hospitalization, 102 (29 percent) developed PTDM within the first year after transplantation [68]. By contrast, only 1 of 28 patients (4 percent) without perioperative hyperglycemia developed PTDM. The risk of PTDM was highest among patients who required insulin perioperatively. Although the incidence and severity of perioperative hyperglycemia depend upon center-specific immunosuppressive protocols (eg, glucocorticoid administration), hyperglycemia nonetheless may help identify patients at increased risk for PTDM [68,69].
•Other – Other peri- and posttransplant risk factors for PTDM include greater human leukocyte antigen (HLA) mismatching, male and deceased-donor allografts. Potential risk factors include polycystic kidney disease [24,70-75] and hypomagnesemia [76-81], although studies have generated inconsistent findings. If present, hypomagnesemia should be corrected.
PRETRANSPLANT EVALUATION —
We agree with recommendations from the 2024 international consensus meeting that advise metabolic screening for all patients prior to kidney transplantation [82]. If screening has not been done as part of the routine pretransplant evaluation, we screen patients once they are waitlisted for transplant. Our evaluation includes the following:
●Identifying risk factors for posttransplantation diabetes mellitus (PTDM) – Kidney transplant candidates should be assessed for potentially modifiable risk factors that may predispose them to insulin resistance and/or pancreatic beta cell dysfunction. Immunosuppressive therapy can increase both insulin resistance and beta cell dysfunction; thus, when possible, efforts to address risk factors should be undertaken as early as possible and ideally prior to transplantation [82]. Risk factors are discussed elsewhere in this topic. (See 'Risk factors' above.)
●Screening for dysglycemia – Most transplant centers measure glycated hemoglobin (A1C) as part of routine pretransplant laboratory testing. (See "Kidney transplantation in adults: Evaluation of the potential kidney transplant recipient", section on 'Laboratory and imaging tests'.)
Some experts advocate for oral glucose tolerance testing (OGTT) prior to transplant once a patient is waitlisted for transplantation [82]. OGTT is preferred over measurement of A1C because A1C is often inaccurate in patients with advanced chronic kidney disease. However, routine screening with OGTT may not be feasible at many transplant centers given its inconvenience and cost.
OGTT enables diagnosis of diabetes and prediabetes (eg, impaired glucose tolerance) (table 1 and table 2), and preoperative impaired glucose tolerance identifies transplant candidates who are at higher risk for PTDM. As an example, in one study of 120 transplant recipients without diabetes, 18 percent of patients had impaired glucose tolerance on OGTT prior to transplantation [83]. Pretransplant impaired glucose tolerance was a risk factor for the development of PTDM (RR 2.4, 95% CI 1.1-5.3), and 11 of 31 patients (35 percent) who developed PTDM had impaired glucose tolerance prior to transplant.
MANAGEMENT OF EARLY POSTTRANSPLANT HYPERGLYCEMIA
Perioperative hyperglycemia — Hyperglycemia is very common in the immediate posttransplant period. Perioperative glycemia is an important risk factor for the development of posttransplantation diabetes mellitus (PTDM), and close monitoring and treatment of hyperglycemia are important aspects of inpatient management in the immediate posttransplant setting.
●Critically ill patients – In the immediate postoperative period, blood glucose levels should be routinely monitored, and patients with hyperglycemia (blood glucose ≥180 mg/dL [10.0 mmol/L]) should be treated with insulin therapy using a standard intravenous (IV) insulin infusion protocol. This approach is consistent with the guidelines for inpatient glycemic management from the American Diabetes Association (ADA) [84-86]. Optimal glycemic targets for the immediate posttransplant period have not been clearly defined. We, and many transplant centers, target blood glucose readings between 140 to 180 mg/dL (7.8 to 10.0 mmol/L) in patients who are critically ill and receiving an insulin infusion [87,88]. (See "Glycemic control in critically ill adult and pediatric patients", section on 'Target range of blood glucose'.)
●Noncritically ill patients
•Glucose-lowering strategy
-Transition from IV to subcutaneous insulin – When patients are stable and no longer critically ill, we usually transition from insulin infusion to a subcutaneous insulin regimen. The transition from IV to subcutaneous insulin should be individualized, and variables such as glucocorticoid dose, allograft function, concurrent infection, and nutritional source (eg, not eating, enteral or parenteral nutrition) should be considered; such factors can contribute to unpredictable glycemic variability and compromise the safety of fixed subcutaneous insulin regimens.
-Choice of subcutaneous insulin regimen – In patients without a previous history of diabetes who require less than 1 to 2 units per hour of IV insulin therapy for the six to eight hours prior to the transition (or <10 units over the prior 24 hours), the use of correction insulin sliding scale before meals and bedtime (or every six hours if not eating) is generally adequate [89]. However, if sliding scale insulin is needed for more than a day or two, the patient’s insulin needs should be reassessed with a low threshold for initiating basal insulin.
In patients with posttransplant hyperglycemia, basal insulin is more effective for achieving glycemic goals and, further, may reduce the likelihood of PTDM. As an example, data from one pilot trial of 50 kidney transplant recipients showed that early basal insulin therapy, compared with short-acting insulin and/or oral glucose-lowering agents, reduced the risk of developing PTDM within the first year after transplant by 73 percent [90]. The authors of this study postulated that early administration of adequate exogenous insulin therapy might protect beta cells from the toxic effects of immunosuppressive therapy and operative stress. A subsequent trial similarly showed that early, post-operative administration of basal insulin neutral protamine hagedorn (NPH) for glucose >140 mg/dl (7.8 mmol/L) numerically reduced the rate of PTDM at 12 months compared with use of sliding scale insulin for glucose >200 mg/dl (11.1 mmol/L) [91], although the difference was not statistically significant. Basal insulin significantly increased the risk of hypoglycemia.
•Glucose targets – Among noncritically ill patients, we target a fasting (premeal) blood glucose of <140 mg/dL (7.8 mmol/L) and random blood glucose of <180 mg/dL (10.0 mmol/L) [84-86,92].
More intensive glycemic targets have not been shown to be beneficial in patients undergoing solid organ transplantation [87,88]. As an example, in one small trial of 104 patients undergoing kidney transplantation that compared intensive (blood glucose target 70 to 110 mg/dL) versus standard (blood glucose target <180 mg/dL) glycemic management, patients in the intensive glycemic management group experienced higher rates of graft rejection, delayed graft function, and hypoglycemia [87].
A detailed approach to the management of hyperglycemia and diabetes in hospitalized patients is presented separately:
●(See "Management of diabetes mellitus in hospitalized patients".)
●(See "Glycemic control in critically ill adult and pediatric patients", section on 'Our approach'.)
The intraoperative management of hyperglycemia during kidney transplantation also is discussed elsewhere. (See "Anesthesia for kidney transplantation", section on 'Management of hyperglycemia'.)
Early (1 to 6 weeks) posttransplant hyperglycemia — Our approach to treating early posttransplant hyperglycemia is largely consistent with the recommendations of the 2024 international consensus meeting on PTDM [82].
Outpatient glucose-lowering strategy — In the early posttransplant period, no high-quality evidence is available to guide the optimal treatment of hyperglycemia. Our approach to initial outpatient treatment is informed by the severity of inpatient hyperglycemia and need for insulin therapy.
●Hyperglycemia requiring ≥20 units daily insulin therapy – In most patients with hyperglycemia requiring a total daily dose of ≥20 units of insulin therapy in the immediate posttransplant period, we continue insulin therapy after hospital discharge. Insulin provides the advantage of easy titration during the first few days after discharge and thereby helps prevent severe glucocorticoid-induced hyperglycemia. Many transplant centers have access to diabetes educators who can provide patients with guidance for insulin therapy, glucose monitoring, and safety precautions.
We typically prefer intermediate-acting NPH insulin, administered as a single daily dose (initially 5 to 10 units and adjusted based on afternoon glucose levels) at the same time as the glucocorticoid dose in the morning [93,94]. With this timing, peak onset of NPH action matches the typical afternoon glucose peak that is observed with glucocorticoid-induced hyperglycemia [95]. An alternative approach is to initiate 0.4 to 0.5 units of NPH insulin daily per prednisone 1 mg (or equivalent). As an example, NPH insulin would be initiated at 16 to 20 units for prednisone 40 mg daily (or equivalent). However, this approach is largely based on expert opinion and increases risk of hypoglycemia.
Treatment alternatives include insulin glargine, administered at night and dose adjusted to achieve the fasting glucose target, or premeal, rapid-acting insulin aspart or insulin lispro, with dosing based on premeal glucose levels and anticipated carbohydrate ingestion. Insulin pump therapy is rarely necessary or indicated in this setting. The duration of insulin treatment depends on the patient's response to therapy as well as subsequent glucose monitoring. Patients whose insulin requirements decrease to <20 units per day after discharge can be transitioned to oral hypoglycemic agents, as discussed immediately below.
●Hyperglycemia requiring <20 units daily insulin therapy – In patients with mild hyperglycemia and low insulin requirements (ie, total daily dose of <20 units of insulin) in the immediate posttransplant period, we prefer oral hypoglycemic agents rather than insulin for outpatient treatment. We prefer agents with lower risk of hypoglycemia and little or no renal excretion, such as meglitinides (eg, repaglinide) or dipeptidyl peptidase 4 (DPP-4) inhibitors. If the choice is made to start a DDP-4 inhibitor, we prefer linagliptin because it is not renally cleared (table 3). If a meglitinide or DPP-4 inhibitor cannot be used, a sulfonylurea with lower risk of hypoglycemia (eg, glipizide) is another option.
Choosing agents that are not renally cleared and confer low risk of hypoglycemia is particularly important during the early posttransplant period, when kidney function fluctuates and dose adjustments for immunosuppressive therapy may be frequent. DPP-4 inhibitors and other options for glucose-lowering therapy are discussed in greater detail below. (See 'Pharmacologic therapy' below.)
Post-discharge monitoring
●Patients requiring glucose-lowering pharmacotherapy – Upon discharge from the hospital, transplant recipients with persistent hyperglycemia, particularly those requiring insulin therapy, should be instructed to perform glucose monitoring at home, either with fingerstick blood glucose monitoring (BGM) or continuous glucose monitoring (CGM) [96,97]. The optimal frequency of fingerstick checks for BGM is unknown for kidney transplant recipients. We suggest initially checking blood glucose once or twice per day, usually before breakfast (fasting) and again in the afternoon or evening before dinner [98]. For patients taking prednisone, checking post-prandial glucose levels is preferred. More frequent testing may be necessary, depending on the severity of hyperglycemia and glucose-lowering regimen. For patients initiating insulin therapy, the approach to monitoring glycemia is reviewed in detail separately. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Monitoring glycemia'.)
Continued monitoring is critical for determining whether posttransplant hyperglycemia is transient or PTDM evolves. (See 'Evaluation and diagnosis of posttransplant diabetes mellitus' below.)
●Patients not requiring glucose-lowering pharmacotherapy – In patients who do not require glucose-lowering therapy upon hospital discharge, we measure a fasting plasma glucose level with each immunosuppressive drug trough measurement. Some centers evaluate for posttransplant hyperglycemia with an afternoon capillary blood glucose level, rather than fasting plasma glucose, in the first few weeks posttransplant. This strategy is based on one observational study that showed that an afternoon (ie, 4:00 PM) capillary glucose level ≥200 mg/dL (11.1 mmol/L) was more sensitive than a fasting plasma glucose level, glycated hemoglobin (A1C), or oral glucose tolerance test (OGTT) for detecting hyperglycemia within the first six weeks after transplantation (46 versus 0, 4, and 12 percent, respectively) [98].
The approach to glycemic monitoring >6 weeks posttransplant is reviewed below. (See 'Evaluation and diagnosis of posttransplant diabetes mellitus' below.)
Glycemic targets — For patients with posttransplant hyperglycemia, optimal glycemic targets are not well defined. We use glycemic targets similar to those established by the ADA for nontransplant patients with diabetes [99]. For most patients, the target A1C is <7 percent if this can be achieved without hypoglycemia. An A1C target of 7 to 7.5 percent is reasonable for patients at higher risk of hypoglycemia. Selection of glycemic targets is reviewed in detail elsewhere. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Blood glucose monitoring and target A1C'.).
If patients are not meeting glycemic targets on initial therapy, we intensify treatment by switching to a more potent agent or adding an additional agent. The approach to medication selection is the same as for patients with PTDM. (See 'Pharmacologic therapy' below.)
EVALUATION AND DIAGNOSIS OF POSTTRANSPLANT DIABETES MELLITUS —
All kidney transplant recipients, irrespective of apparent metabolic risk, should be routinely monitored for posttransplantation diabetes mellitus (PTDM). Early evaluation and close monitoring are critical, as emerging evidence suggests that PTDM may be reversible when diagnosed and treated early [18,100]. The physiologic basis of PTDM includes reduced insulin secretion, increased insulin resistance, and diminished glucagon suppression during hyperglycemia [101].
Most kidney transplant recipients with posttransplant hyperglycemia will experience resolution of hyperglycemia once the doses of immunosuppressive agents are reduced over time [18]. However, some patients will develop chronic hyperglycemia and meet diagnostic criteria for PTDM. (See 'Diagnostic criteria' below.)
Glycemic monitoring — Glycemic monitoring is essential in all patients, irrespective of whether they experienced postoperative hyperglycemia.
Early (>6 weeks to <3 months) posttransplant — From 6 weeks to 3 months posttransplantation, our approach to glycemic monitoring is the same as for the first 6 weeks posttransplant. For patients who are taking glucose-lowering pharmacotherapy, the approach to monitoring depends on the specific regimen used. For patients not taking glucose-lowering pharmacotherapy, a fasting glucose level is typically obtained with each immunosuppressive drug trough measurement. (See 'Post-discharge monitoring' above.)
Subsequent monitoring — After ≥3 months posttransplant, an A1C may be measured to assess glycemia [3,102]. We typically check an A1C at 3, 6, and 12 months posttransplant and then yearly thereafter in patients who have not developed PTDM. A1C should not be used to evaluate for PTDM prior to three months posttransplant, since a normal test cannot exclude the diagnosis in the setting of posttransplant anemia, recovery from pretransplant anemia, or dynamic kidney allograft function [98]. A1C may not be valid until new hemoglobin has been synthesized and glycated for at least three months in the posttransplant setting [103]. If anemia persists or fluctuates, A1C should not be used to assess glycemic status, as a low or normal value may be falsely reassuring.
Although less convenient, an oral glucose tolerance test (OGTT) remains the gold standard for diagnosing PTDM [102]. International consensus guidance advocates for OGTT to be performed at approximately three months posttransplantation and annually thereafter [82]. In studies that have evaluated the incidence of impaired glucose tolerance and PTDM using serial posttransplant OGTTs, most patients who develop persistent PTDM could be identified within three months of transplantation; conversely, patients with a normal OGTT three to 12 months posttransplant were at low risk for developing late PTDM [11,27].
Criteria for the diagnosis of PTDM are presented immediately below.
Diagnostic criteria — PTDM should be diagnosed only once patients are on a stable maintenance immunosuppression regimen with stable kidney allograft function, and it should not be diagnosed in the presence of acute infection [3]. Transient posttransplant hyperglycemia is very common (up to 90 percent of patients) in the immediate-to-early posttransplant period but usually resolves within the first few weeks after transplantation. Thus, a formal diagnosis of PTDM should not be made in patients within the first six weeks after transplantation [3]. However, if the patient fulfills diagnostic criteria for PTDM beyond six weeks posttransplantation, a formal diagnosis of PTDM is made.
●Patients taking glucose-lowering pharmacotherapy – If patients continue to require insulin therapy >6 weeks posttransplant, they generally are diagnosed with PTDM provided their kidney allograft function and immunosuppressive regimen are stable.
For patients using an oral agent only who are meeting glycemic targets, we typically stop glucose-lowering treatment and continue glycemic monitoring. (See 'Glycemic monitoring' above.)
●Patients not taking glucose-lowering pharmacotherapy – Diagnostic criteria for PTDM are the same criteria used for nontransplant patients (table 1). In the absence of overt, symptomatic hyperglycemia, diagnosis requires two test results that meet these criteria. (See "Screening for type 2 diabetes mellitus and prediabetes", section on 'Test interpretation and follow-up'.)
•Symptoms of diabetes plus random plasma glucose ≥200 mg/dL (11.1 mmol/L). Symptoms include polyuria, polydipsia, and unexplained weight loss.
•Fasting plasma glucose ≥126 mg/dL (7.0 mmol/L).
•Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT.
•A1C ≥6.5 percent (≥3 months posttransplant).
The diagnosis of prediabetes is also the same in transplant recipients as in nontransplant patients (table 2). Nonetheless, the diagnostic accuracy of A1C is compromised in the posttransplant setting; for example, one meta-analysis found low diagnostic sensitivity for A1C, even when a lower cutoff value of 6.2 percent was used [104].
MANAGEMENT OF POSTTRANSPLANT DIABETES MELLITUS —
In patients with posttransplantation diabetes mellitus (PTDM) or prediabetes, we and most experts take a stepwise approach to managing chronic hyperglycemia [82]. This starts with lifestyle modification, which includes dietary modification, weight reduction, and increased physical activity, and is followed by pharmacologic therapy. In kidney transplant recipients with PTDM, the goals of therapy are to improve glycemic management and to manage risk factors for cardiovascular disease. (See 'Prognosis' below.)
Lifestyle modification — For all kidney transplant recipients with PTDM, we suggest lifestyle interventions focusing on dietary modification, weight reduction, and physical activity. Lifestyle modification should be attempted along with the initiation of pharmacologic therapy for PTDM, as early pharmacologic treatment may lead to PTDM resolution in kidney transplant recipients, and lifestyle intervention alone may provide less benefit in kidney transplant recipients than in individuals with type 2 diabetes.
We also suggest lifestyle intervention for patients with risk factors for diabetes, including prediabetes, sedentary behavior, hypertension, hyperlipidemia, and/or obesity. Studies examining the effects of lifestyle interventions in the transplant population are limited [105,106], but available data have not demonstrated beneficial effects on insulin secretion or insulin sensitivity after six months of follow-up [105]. These recommendations are largely based on the benefits of lifestyle modification evident in nontransplant patients with type 2 diabetes; this evidence and detailed approaches to lifestyle intervention are discussed in more detail separately.
●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Exercise'.)
Pharmacologic therapy
Choice of initial therapy — For kidney transplant recipients who are already taking pharmacotherapy for posttransplant hyperglycemia, we continue current therapy if the patient is meeting glycemic goals. If patients are not meeting glycemic goals, treatment should be intensified. (See 'Management of early posttransplant hyperglycemia' above and 'Persistent hyperglycemia' below.)
For patients not taking glucose-lowering pharmacotherapy, evidence is insufficient to support a specific first-line agent for the chronic management of hyperglycemia in PTDM [5,107,108]. Our approach is discussed below.
Patients with unstable allograft function
●Assessing glycemia – A1C may be unreliable in the posttransplant setting, particularly if allograft function is unstable. For patients performing blood glucose monitoring (BGM) with fingerstick and a glucose meter, BGM values may be a more reliable metric. In general, for individuals with an A1C goal <7 percent, the following targets may be used:
•Fasting glucose values between 80 to 130 mg/dL (4.4 to 7.2 mmol/L)
•Postprandial (90 to 120 minutes after a meal) glucose values <180 mg/dL (10 mmol/L)
Continuous glucose monitoring metrics, including time spent in the target glucose range (70 mg/dL to 180 mg/dL [3.9 to 18 mmol/L]) or the glucose management indicator (GMI), are also reasonable to use in this setting. Other options for assessing chronic glycemia when A1C is unreliable are reviewed separately. (See "Measurements of chronic glycemia in diabetes mellitus", section on 'Other biomarkers'.)
●Glycemia well above target – Kidney transplant recipients with PTDM who have unstable kidney allograft function and glycemia well above target should generally be treated with insulin. Insulin therapy can be rapidly titrated as allograft function fluctuates and glucocorticoid therapy is adjusted. The approach to insulin therapy is the same as for managing type 2 diabetes and is reviewed in detail separately. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Designing an insulin regimen'.)
●Mild hyperglycemia – For patients with mild hyperglycemia, a dipeptidyl peptidase 4 (DPP-4) inhibitor is a reasonable option. In the posttransplant setting, linagliptin is preferred among DDP-4 inhibitors because it has minimal renal clearance. Further, in one retrospective study in kidney transplant recipients, linagliptin was associated with greater A1C reduction compared with vildagliptin or sitagliptin (-1.40 versus -0.38 and -0.53 percent, respectively) and with minimal change in cyclosporine trough levels [109].
If hyperglycemia is primarily postprandial and glycemia is close to target, meglitinide therapy (eg, repaglinide) is also a reasonable alternative. Meglitinides are effective in some patients with PTDM. One six-month study found that repaglinide lowered mean A1C levels (7.6 to 5.8 percent) in 14 of 23 patients with PTDM, with the remainder eventually requiring insulin therapy [110]. However, limitations include two- or three-times daily dosing and unpredictable glucose-lowering efficacy in this population. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Meglitinides'.)
These treatment options are reviewed in detail elsewhere. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus", section on 'Choice of DPP-4 inhibitor' and "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Meglitinides'.)
Patients with stable allograft function — For most kidney transplant recipients with PTDM who have stable kidney allograft function, we suggest a sodium-glucose cotransporter 2 (SGLT2) inhibitor (dapagliflozin, empagliflozin, canagliflozin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist with cardiovascular and kidney benefits (liraglutide, dulaglutide, subcutaneous semaglutide) as initial glucose-lowering therapy. Beyond glycemic management, these agents have been shown to have protective cardiovascular and/or kidney benefits. These effects have been strongly demonstrated in nontransplant populations, but available data suggest benefit in transplant recipients as well [111-113]. In addition, GLP-1 receptor agonists have been shown to confer weight loss benefits in patients with obesity. If SGLT2 inhibitors or GLP-1 agents are contraindicated or not available, other reasonable alternatives for first-line therapy include metformin, a DPP-4 inhibitor, a sulfonylurea, or a meglitinide.
For patients who need greater initial glucose lowering (eg, A1C >9 percent, fasting glucose >250 mg/dL [13.9 mmol/L]), insulin therapy is preferred. However, given the potential side effects of weight gain and hypoglycemia, we typically reserve insulin therapy for patients with PTDM and either severe hyperglycemia or persistent hyperglycemia despite treatment with another agent. (See 'Persistent hyperglycemia' below.)
The choice of initial therapy is informed by factors including glucose-lowering efficacy, route and frequency of administration, cost, hypoglycemia risk, and effect on body weight (table 4). The presence of any of the following also may influence agent selection:
●History of heart failure – SGLT2 inhibitors are preferred in patients with comorbid heart failure, given their protective benefits in nontransplant patients with heart failure. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
●History of atherosclerotic cardiovascular disease (ASCVD) – Cardioprotective GLP-1 receptor agonists are preferred in patients with existing ASCVD, given evidence that selected agents in these classes can reduce ASCVD outcomes in nontransplant populations. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
Selected SGLT2 inhibitors also have protective effects in nontransplant populations with existing ASCVD. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Cardiovascular effects'.)
●Reduced kidney allograft function – SGLT2 inhibitors or selected GLP-1 receptor agonists may be preferred in patients with reduced kidney allograft function, given their protective kidney benefits in nontransplant patients. SGLT2 inhibitors lower glucose by promoting glucosuria, so their glucose-lowering efficacy depends on estimated glomerular filtration rate (eGFR). At an eGFR below 30 to 45 mL/min/1.73 m2, these agents provide little glucose-lowering benefit and therefore are not preferred initial therapy. However, they may be used for non-glycemic benefits. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus", section on 'Kidney outcomes'.)
●Obesity – GLP-1 receptor agonists may be preferred in kidney transplant recipients with obesity since these agents have weight loss benefits, in addition to high glucose-lowering efficacy. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Weight loss'.)
More details on the use of glucose-lowering agents as well as supportive evidence in kidney transplant recipients are discussed below:
●SGLT2 inhibitors – SGLT2 inhibitor mechanism of action, treatment precautions, and clinical efficacy in nontransplant populations are reviewed in detail separately. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)
Data examining the safety and efficacy of SGLT2 inhibitors in kidney transplant recipients with PTDM are limited but increasing [114-118]. Two small trials in kidney transplant recipients found that SGLT2 inhibitor therapy was well tolerated up to approximately 10 months of follow-up. Although these trials demonstrated only modest glucose lowering, observational studies suggest that SGLT2 inhibitor treatment is associated with benefits beyond glycemic management in kidney transplant recipients, including protection from allograft failure and major cardiovascular events [118-121]. As an example, in one study that compared outcomes among 2083 kidney transplant recipients with diabetes (475 with PTDM, 1608 with pretransplant diabetes) who were or were not receiving an SGLT2 inhibitor, use of an SGLT2 inhibitor was associated with lower risks of death-censored graft failure (adjusted hazard ratio [HR] 0.31, 95% CI 0.09-0.98) and doubling of serum creatinine (adjusted HR 0.45, 95% CI 0.23-0.88) [118]. Approximately 16 percent of recipients receiving an SGLT2 inhibitor experienced an acute decrease in eGFR of >10 percent during the first month of use, but the eGFR recovered thereafter. The initial decrease in eGFR should not warrant discontinuation or preclude use of an SGLT2 inhibitor [119].
●GLP-1 receptor agonists – Use of GLP-1 receptor agonists has grown in kidney transplant recipients, and available data support the glycemic efficacy and possible protective effects on kidney allograft function and cardiovascular outcomes [122,123]. GLP-1 receptor agonist-based therapy mechanisms of action, treatment precautions, and clinical efficacy in nontransplant populations are reviewed in detail separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)
In one retrospective study of 17 kidney transplant recipients (11 with PTDM, 3 with pretransplant diabetes), treatment with a GLP-1 receptor agonist (mostly liraglutide) was associated with a reduction in the total daily insulin dose and risk of hypoglycemia in patients who were on therapy for at least 12 months [124]. Kidney allograft function remained stable, and tacrolimus dosing did not require adjustment. Five patients (29 percent) discontinued therapy, four due to adverse effects and one due to uncontrolled hyperglycemia. In another retrospective study that included 118 solid organ transplant recipients (70 percent kidney transplant) who used GLP-1 receptor agonist therapy for at least three months, GLP-1 receptor agonist treatment was associated with reductions in fasting glucose, A1C, and body weight [125].
Several other single-center non-randomized studies have shown similar results, suggesting their safe and effective use, although rates of discontinuation (primarily due to gastrointestinal side effects) of up to 30 percent were seen in some studies. One study from Japan noted that GLP-1 receptor agonists resulted in lower eGFR reduction compared with non–GLP-1 receptor agonists and may contribute to better kidney allograft survival after kidney transplantation in patients with pre-existing type 2 diabetes [111].
●Other agents
•Metformin – In contrast to management of nontransplant patients with type 2 diabetes, we generally do not use metformin as first-line monotherapy to treat PTDM, given the protective cardiovascular and kidney effects of agents in other drug classes. However, metformin may be used in combination with a GLP-1 receptor agonist or SGLT2 inhibitor in patients who need additional glucose lowering. Metformin is also a reasonable alternative if preferred agents are not available or not tolerated. Although a rare event, the risk of lactic acidosis increases with metformin use when kidney function is impaired [126]. Nonetheless, some experts use metformin in transplant recipients based upon data from observational studies and one small randomized trial that have shown favorable patient and graft outcomes as well as safety and efficacy [127-129]. Metformin therapy, including contraindications to use, is discussed in detail separately. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)
•DPP-4 inhibitors – Limited data suggest that dipeptidyl peptidase-4 (DPP-4) inhibitors are generally safe and effective in kidney transplant recipients. The use of these agents may be limited by their high cost and limited glucose-lowering effectiveness. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)
We generally reserve use of DPP-4 inhibitors for patients with unstable allograft function and mild hyperglycemia. (See 'Patients with unstable allograft function' above.)
Sitagliptin, linagliptin, and vildagliptin have been evaluated in kidney transplant recipients [109,130-133]. Three reports have documented the safety and efficacy of sitagliptin for treatment of PTDM in kidney transplant recipients; both first- and second-phase insulin secretion responses increased significantly in sitagliptin-treated patients [130,131,133]. Although sitagliptin does not cause hypoglycemia, it may prolong the QT interval, especially if used with cyclosporine.
•Sulfonylureas – Among the sulfonylureas, glipizide and glimepiride are preferred to glyburide when the eGFR is <50 mL/min/1.73 m2 because glyburide may accumulate with kidney function impairment, resulting in hypoglycemia. We usually begin with glipizide at 2.5 to 5 mg orally daily and then advance to 10 mg twice per day as necessary to achieve target A1C. Glipizide has minimal renal excretion and does not change cyclosporine levels in kidney transplant recipients [5]. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Sulfonylureas'.)
•Meglitinides – Meglitinides, such as repaglinide, are effective in some patients with PTDM. They are a reasonable choice for patients who predominantly have postprandial hyperglycemia, and their short duration of action is an advantage in patients with unstable or impaired allograft function. (See 'Patients with unstable allograft function' above.)
Persistent hyperglycemia — For patients with PTDM and persistent hyperglycemia despite treatment with one glucose-lowering agent, the following strategies are reasonable:
●Combine two oral agents – Many glucose-lowering agents may be used in combination. However, due to similar mechanisms of action, the following agents should not be used together:
•Sulfonylureas and meglitinides
•GLP-1 receptor agonist-based therapy and DPP-4 inhibitors
We generally avoid the use of pioglitazone in transplant recipients as it may worsen immunosuppression-associated bone loss and can cause or worsen edema, which may necessitate the use of diuretics and increase risk of calcineurin inhibitor toxicity. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)
Alpha-glucosidase inhibitors may be used as a second- or third-line agent in patients for whom avoiding hypoglycemia is a primary goal of care. However, these agents typically have low glucose-lowering efficacy, and use is often limited by gastrointestinal side effects. (See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus".)
●Start injectable GLP-1 receptor agonist therapy – Injectable GLP-1 receptor-based agents generally confer more glucose lowering than oral agents, including oral semaglutide. Depending upon current glucose-lowering therapy, injectable GLP-1 receptor agonist-based agents may be added or substituted. Pretreatment considerations and dosing for GLP-1-based therapies are reviewed separately. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus", section on 'Suggested approach to the use of GLP-1 receptor agonist-based therapies'.)
●Start insulin therapy – Many patients will require insulin therapy, especially if blood glucose levels exceed 250 mg/dL (13.9 mmol/L). We initiate insulin therapy if oral agents have not been effective or have been accompanied by unacceptable side effects, or if A1C is >9 percent. Insulin therapy should generally not be combined with a sulfonylurea or meglitinide. The decision to combine insulin therapy with other agents or use as monotherapy is reviewed in detail separately. (See "Insulin therapy in type 2 diabetes mellitus", section on 'Combination therapy versus insulin monotherapy'.)
Even with small doses of glucocorticoids (eg, prednisone 5 mg/day or equivalent) taken in the morning, a late-afternoon or early-evening peak in glucose concentration is often much higher than fasting glucose concentrations. In this setting, intermediate-acting insulin (eg, insulin NPH) administered in the morning is an effective management strategy that allows for rapid titration as glucocorticoid doses are adjusted.
The overall approach to insulin therapy is the same as for nontransplant patients with diabetes. (See "Insulin therapy in type 2 diabetes mellitus" and "General principles of insulin therapy in diabetes mellitus".)
Persistently low allograft function — For patients with persistently low allograft function (ie, eGFR <30 mL/min/1.73 m2), cautious use of a GLP-1 receptor agonist can achieve glucose lowering with low risk of hypoglycemia. If the patient has mild hyperglycemia, some experts would start with a DPP-4 inhibitor and escalate to a GLP-1 receptor agonist if hyperglycemia is not well controlled. SGLT-2 inhibitors are relatively ineffective at lowering glycemia in patients with a low eGFR and are associated with an increased risk of diabetic ketoacidosis. We typically avoid sulfonylureas given the high risk of hypoglycemia. Other options for glucose management are reviewed in detail elsewhere. (See "Management of hyperglycemia in patients with type 2 diabetes and advanced chronic kidney disease or end-stage kidney disease", section on 'Approach to pharmacologic therapy'.)
Adjustment of immunosuppression — In patients with PTDM, adjusting immunosuppression therapy may be considered to help improve glycemia. However, the potential benefit of altering immunosuppressive agents must be weighed against the risk of allograft rejection and is not recommended as standard-of-care management. We typically consult with the transplant team about possible modifications to immunosuppressive therapy if patients are unable to meet glycemic targets despite ≥3 glucose-lowering agents or require high-dose insulin therapy (eg, >2 unit/kg).
●Glucocorticoids – In general, the glucocorticoid dose should be decreased as soon as possible posttransplant, but complete glucocorticoid withdrawal is not recommended. (See "Kidney transplantation in adults: Maintenance immunosuppressive therapy", section on 'Glucocorticoids'.)
Prednisolone dose reduction to 5 mg/day at one year has been associated with a decrease in the prevalence of glucose intolerance from 55 to 34 percent [47]. Although complete glucocorticoid withdrawal can reduce the incidence of PTDM, a significant percentage of patients suffer a rejection episode requiring reinstitution of glucocorticoid therapy [134]. One study also found no improvement in insulin sensitivity when decreasing the prednisolone dose from 5 mg to complete withdrawal [51]. Though not well studied in transplant recipients, divided dosing may reduce variability and peak of glucocorticoid-induced hyperglycemia [135].
●Tacrolimus – Compared with cyclosporine, the use of tacrolimus is associated with higher rates of PTDM, particularly with tacrolimus trough levels >15 ng/mL in the first month posttransplant. Thus, in patients with PTDM and persistent hyperglycemia, consideration should be given to reducing the tacrolimus dose, particularly if evidence of toxicity is present (eg, tremor, headache, hyperkalemia, acidemia) and the patient is at least 6 to 12 months posttransplant. As an alternative to tacrolimus dose reduction, switching to a long-acting formulation may help improve glycemia, although this potential benefit has not been clearly demonstrated [136].
•Patients meeting glycemic targets – We generally do not switch patients with PTDM from tacrolimus to cyclosporine for glycemic benefit alone, since the glycemic effects of tacrolimus may resolve even if the agent is continued. In one study, for example, 70 percent of White patients and 20 percent of Black patients were able to discontinue insulin without discontinuing tacrolimus or glucocorticoids [137]. In addition, one large review reported improved graft survival with tacrolimus therapy despite the increased rate of PTDM seen with tacrolimus and the association of PTDM with decreased graft survival [19]. Another registry analysis of the United States Renal Data System (USRDS) database of nearly 50,000 patients transplanted between January 1998 and December 2002 showed that diabetes was associated with worse patient and graft survival; nonetheless, these outcomes did not differ between tacrolimus- and cyclosporine-treated patients despite a higher incidence of PTDM among those who received tacrolimus [138].
•Patients with persistent hyperglycemia – Switching to cyclosporine is a reasonable strategy if diabetes remains difficult to manage despite use of lower-dose tacrolimus [2]. Some studies suggest that switching from tacrolimus to cyclosporine may improve glycemia and potentially resolve PTDM. A small trial randomly assigned 67 kidney transplant recipients with PTDM taking tacrolimus to cyclosporine conversion versus tacrolimus continuation and demonstrated improvement in A1C with cyclosporine treatment, as well as a numerically higher rate of diabetes reversal [139]. Another randomized trial showed the benefit of switching tacrolimus to cyclosporine in recipients with PTDM, as 34 percent of participants in the cyclosporine conversion group versus 10 percent in the tacrolimus continuation group showed PTDM resolution [140].
Conversion to mTOR inhibitors (sirolimus, everolimus) is not recommended; sirolimus may worsen insulin resistance and glycemia [67,141].
Conversion to belatacept is not generally performed for the indication of PTDM alone. However, patients who are converted from tacrolimus to belatacept for other indications (eg, tacrolimus-related side effects) may experience an improvement in glycemia [142].
Monitoring
●Home glucose monitoring – Kidney transplant recipients with PTDM that requires glucose-lowering therapy should monitor glucose levels at home. This may entail fingerstick and use of a glucose meter (ie, blood glucose monitoring [BGM]) or continuous glucose monitoring (CGM). The choice between BGM and CGM depends on the intensity of medical therapy, patient preferences, risk of hypoglycemia, and cost. CGM is preferred in patients with reduced allograft function in whom A1C is not a reliable metric of glycemia. Options for ambulatory glucose monitoring are discussed in detail separately. (See "Glucose monitoring in the ambulatory management of nonpregnant adults with diabetes mellitus".)
●Other glycemic metrics – In patients with PTDM and normal kidney allograft function, we also measure A1C every three months. The optimal glycemic target for kidney transplant recipients with PTDM is not known. In general, the goals for glycemic management in kidney transplant recipients are similar to those in nontransplant patients with diabetes and should take into account such factors as duration of diabetes, comorbid conditions, risk for hypoglycemia, and life expectancy. A reasonable goal for most patients, as recommended by the ADA, is an A1C of <7 percent. This goal should be set somewhat higher (eg, <8 percent) for older patients and those with a limited life expectancy. The Kidney Disease: Improving Global Outcomes (KDIGO) guidelines recommend an A1C goal of 7 to 7.5 percent for kidney transplant recipients [143]. (See "Glycemic management and vascular complications in type 2 diabetes mellitus", section on 'Choosing a glycemic target'.)
The A1C assay will not reliably measure average glucose levels in the setting of anemia, especially if erythropoietin replacement is administered, or in the setting of reduced allograft function. In such cases, alternative metrics of chronic glycemia should be used; these are reviewed separately. (See "Measurements of chronic glycemia in diabetes mellitus".)
●Additional monitoring and medical management – Other aspects of monitoring and routine medical care for individuals with diabetes are shown in the table and reviewed in detail separately (table 5). (See "Overview of general medical care in nonpregnant adults with diabetes mellitus".)
PROGNOSIS
●Patient survival – The development of posttransplantation diabetes mellitus (PTDM) adversely affects patient survival in most studies [19-21,53,144-153]:
•In one study, one-year patient survival was 83 and 98 percent in those with and without PTDM, respectively [20]. A subsequent report found that five-year survival with PTDM was 87 versus 93 percent among patients without diabetes [40]. However, these studies were performed in the era of high-dose glucocorticoid use and cyclosporine-based regimens.
•However, a subsequent analysis of 628 kidney transplant recipients followed for a median of 56 months after transplant found no association between new-onset PTDM and death with a functioning graft [154]. Tighter glucose monitoring, more intensive glycemic control, and glucocorticoid minimization may have explained the reduced impact of PTDM on patient survival in this study.
The development of PTDM correlates with increased cardiovascular mortality, which is the most prevalent cause of poor long-term survival [19,155-160]. The increased relative risk (RR) for death from cardiovascular disease ranges from 1.5 to 3 among those who develop PTDM versus those without diabetes [19,156,158]. Some of the excess risk is associated with coexistence of other cardiovascular risk factors, particularly increased age and dyslipidemia [158].
●Allograft survival – Studies evaluating whether PTDM decreases long-term allograft survival have shown conflicting findings. In one study, for example, graft survival at 12 years was 48 and 70 percent in those with and without PTDM, respectively (relative risk [RR] of graft loss 3.72) [161]. However, in subsequent cohort studies, the rates of allograft failure were comparable between kidney transplant recipients with and without PTDM [14-16]. This apparent improvement in allograft survival may in part reflect the advent of kidney protective agents for glucose lowering or changes in immunosuppressive strategies over time.
Most, if not all, of the reported adverse effect of PTDM on allograft survival is due to the increase in mortality associated with PTDM. Other mechanisms by which PTDM may decrease allograft survival are not clearly defined and may include diabetic kidney disease [162] or increased rates of rejection due to changes in immunosuppressive therapy intended to improve glycemia [161].
●Infections – PTDM has been associated with an increased risk for infection and sepsis, with hyperglycemia possibly altering the immune response [20,40,148,161,163]. Urinary tract infection, pneumonia, and cytomegalovirus (CMV) have also been reported to occur at increased rates with diabetes [20,40,148].
●Diabetes-related complications – Metabolic and microvascular complications observed in nontransplant patients with diabetes are also observed in those who develop PTDM. This was shown in a retrospective study of 4105 patients who developed PTDM by three years posttransplantation [164]. Ophthalmic and neurologic complications occurred in 8 and 16 percent of patients, respectively [164]. These complications developed at an accelerated rate compared with those in nontransplant patients.
Diabetic complications may occur at a faster rate in those treated with tacrolimus compared with cyclosporine [164]. (See 'Risk factors' above.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Kidney transplantation".)
SUMMARY AND RECOMMENDATIONS
●Terminology – Posttransplant diabetes mellitus (PTDM) describes the diagnosis of diabetes after transplantation, irrespective of whether it may have been present but undetected before transplantation. (See 'Terminology' above.)
●Risk factors – Pretransplant risk factors for PTDM include obesity, increased age (≥40 to 45 years), history of gestational diabetes, or a first-degree relative with type 2 diabetes. The most important posttransplant risk factor for PTDM is immunosuppressive therapy, which can contribute to both reduced insulin secretion and increased insulin resistance. (See 'Risk factors' above.)
●Pretransplant evaluation – All patients should undergo metabolic screening prior to transplant. Our evaluation includes identifying risk factors for PTDM and measuring glycated hemoglobin (A1C) to assess for dysglycemia. Some experts advocate for oral glucose tolerance testing (OGTT) once a patient is waitlisted for transplantation; however, routine screening with OGTT may not be feasible at many transplant centers given its inconvenience and cost. (See 'Pretransplant evaluation' above.)
●Early posttransplant hyperglycemia
•Perioperative – Hyperglycemia is very common in the immediate posttransplant period. Insulin therapy is preferred in this setting, and glycemic targets are the same as for other critically ill and noncritically ill hospitalized patients. (See 'Perioperative hyperglycemia' above and "Glycemic control in critically ill adult and pediatric patients".)
•Early (1 to 6 weeks) posttransplant – For most patients with hyperglycemia requiring a total daily dose of ≥20 units of insulin therapy in the immediate posttransplant period, we suggest continuing insulin therapy after hospital discharge rather than switching to oral hypoglycemic agents (Grade 2C). For patients with mild hyperglycemia and low insulin requirements (ie, total daily dose of <20 units of insulin) in the immediate posttransplant period, we suggest oral hypoglycemic agents rather than insulin for outpatient treatment (Grade 2C). We prefer agents with lower risk of hypoglycemia and little or no renal excretion, such as meglitinides (eg, repaglinide) or dipeptidyl peptidase 4 (DPP-4) inhibitors. (See 'Outpatient glucose-lowering strategy' above.)
●Evaluation and diagnosis of PTDM
•Glycemic monitoring – Glycemic monitoring is essential in all patients, irrespective of whether they experienced postoperative hyperglycemia. We typically check an A1C at 3, 6, and 12 months posttransplant and then yearly thereafter. A1C should not be used to evaluate for PTDM prior to three months posttransplant, since a normal test cannot exclude the diagnosis in the setting of posttransplant anemia, recovery from pretransplant anemia, or dynamic kidney allograft function. (See 'Glycemic monitoring' above.)
•Diagnostic criteria – PTDM should be diagnosed only once patients are on a stable maintenance immunosuppression regimen with stable kidney allograft function, and it should not be diagnosed in the presence of acute infection. Diagnostic criteria for PTDM are the same criteria used for nontransplant patients (table 1). In the absence of overt, symptomatic hyperglycemia, diagnosis requires two test results that meet these criteria. (See 'Diagnostic criteria' above.)
●PTDM management
•Lifestyle intervention – Lifestyle interventions (dietary modification, weight reduction, physical activity) are appropriate for all patients with diabetes, including those with PTDM. Lifestyle modification should be attempted along with the initiation of pharmacologic therapy for PTDM. (See 'Lifestyle modification' above.)
•Pharmacologic therapy
-Unstable allograft function – For patients with PTDM who have unstable kidney allograft function and glycemia well above target, we suggest insulin rather than an oral hypoglycemic agent (Grade 2C). Insulin therapy can be rapidly titrated as allograft function fluctuates and glucocorticoid therapy is adjusted. (See 'Patients with unstable allograft function' above.)
For patients with mild hyperglycemia, we suggest a dipeptidyl peptidase 4 (DPP-4) inhibitor rather than insulin (Grade 2C). In the posttransplant setting, linagliptin is preferred among DDP-4 inhibitors because it has minimal renal clearance (table 3).
-Stable allograft function – For most patients with PTDM who have stable kidney allograft function, we suggest a sodium-glucose cotransporter 2 (SGLT2) inhibitor (dapagliflozin, empagliflozin, canagliflozin) or an injectable glucagon-like peptide-1 (GLP-1) receptor agonist with cardiovascular and kidney benefits (liraglutide, dulaglutide, subcutaneous semaglutide) as initial glucose-lowering therapy (Grade 2C). Beyond glycemic management, these agents have been shown to have protective cardiovascular and/or kidney benefits (table 4). These effects have been strongly demonstrated in nontransplant populations, but available data suggest benefit in transplant recipients as well. For patients with persistently low allograft function (eg, estimated glomerular filtration rate <30 mL/min/1.73 m2), a GLP-1 receptor agonist may be more effective. (See 'Patients with stable allograft function' above.)
●Monitoring – In patients with PTDM and normal kidney allograft function, we measure A1C every three months (table 5). A reasonable goal for most patients, as recommended by the ADA, is an A1C of <7 percent. (See 'Monitoring' above.)
