Version June 2024
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 screening 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
●Posttransplantation diabetes mellitus (PTDM) – PTDM describes the presence of diabetes after transplantation, irrespective of timing of diagnosis or whether it was present but undetected before transplantation. We and others [1] prefer this term over new-onset diabetes after transplantation (NODAT) because NODAT does not include patients who may have had diabetes prior to transplant that was unrecognized. However, we prefer to differentiate diabetes that was undiagnosed during the pretransplant period (typically type 2 diabetes) from diabetes that develops in the posttransplant period, given the differences in the pathophysiology of these conditions [2-5]. Importantly, the term PTDM excludes patients with transient posttransplant hyperglycemia.
●New-onset diabetes mellitus after transplantation (NODAT) – This term was established by an international consensus guideline in 2003 to describe the pathophysiological consequences of transplantation on glucose metabolism [6]. The guidelines recommended that the definition and diagnosis of NODAT be based upon the standard World Health Organization (WHO) and American Diabetes Association (ADA) criteria for the diagnosis of diabetes mellitus and impaired glucose tolerance (table 1 and table 2) [7,8]. By definition, the term NODAT does not include patients who may have had diabetes prior to transplant that was unrecognized. Many transplant centers do not screen for undiagnosed diabetes during the pretransplant evaluation, so pretransplant diabetes is not accurately identified.
●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 administration of high-dose glucocorticoids (figure 1) [9]. In most cases, posttransplant hyperglycemia is transient and 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 PTDM.
●Other terms – Terms in use following the initial recognition of hyperglycemia after kidney transplantation in 1964 [10] include posttransplantation hyperglycemia and diabetes after transplantation [2]. However, these terms are generally not used.
EPIDEMIOLOGY — The reported incidence of posttransplantation diabetes mellitus (PTDM) is variable and must be interpreted in the context of definition used, time from transplant, study population, and immunosuppressive agents used for individual studies. Studies that were published prior to the development of the 2003 consensus definition for new-onset diabetes after transplantation (NODAT) described above reported rates ranging from 7 to 46 percent [11-14]. (See 'Terminology' above.)
Several studies have provided incidence estimates of NODAT defined by the 2003 international consensus guidelines, including the use of the oral glucose tolerance test (OGTT) [15-19]. A substantial number of patients who were classified as having PTDM in these reports became normoglycemic without any medical therapy, suggesting that their hyperglycemia was transient and that incidence was overestimated in these reports. However, even transient perioperative hyperglycemia may suggest a higher risk for the future development of PTDM (see 'Modifiable risk factors' below). Overall, studies that use the existing criteria for diagnosis suggest that up to one-third of nondiabetic kidney transplant recipients develop prediabetes or PTDM by six months posttransplantation [15,16,19,20].
Although earlier reports suggested an increasing incidence of PTDM [14], subsequent data from the Organ Procurement and Transplant Network/Scientific Registry of Transplant Recipients (OPTN/SRTR) showed that the prevalence of PTDM at one year posttransplant decreased from 10 percent in 2007 to under 4 percent in 2016, while the five-year incidence of PTDM decreased from approximately 16 percent in 2007 to 10 percent in 2012 [21,22]. Long-term studies have reported two- to five-year incidence rates ranging from 18 to 33 percent [23,24].
RISK FACTORS
Modifiable risk factors
●Immunosuppressive agents – Immunosuppressive agents that contribute to posttransplantation diabetes mellitus (PTDM) include glucocorticoids, calcineurin inhibitors, and mammalian (mechanistic) target of rapamycin (mTOR) inhibitors:
•Glucocorticoids – Higher doses of glucocorticoids among kidney transplant patients have been associated with the development of PTDM [11,22,25-27]. In one study of 173 patients, for example, there was a significant relationship between prednisolone dose and two-hour serum glucose levels measured for oral glucose tolerance tests (OGTTs) [25]. The risk of developing PTDM was 5 percent per 0.01 mg/kg per day increase in prednisolone dose. The progressive reduction in daily glucocorticoid dose may explain the significantly lower rates of PTDM compared with those reported several decades ago (46 percent in 1979) [11,22,25-27].
However, complete glucocorticoid withdrawal has not been clearly shown to reduce the incidence of PTDM, as studies comparing glucocorticoid withdrawal with glucocorticoid continuation have not produced consistent results [28-31]. A significant percentage of patients suffer an episode of acute rejection following glucocorticoid withdrawal, requiring reinstitution of glucocorticoid therapy, often with high doses; pulsed, high-dose glucocorticoid therapy for acute rejection increased the risk for PTDM [32]. Thus, adjustment of immunosuppression therapy aimed at improving glucose tolerance must be weighed against the risk of allograft rejection.
•Calcineurin inhibitors – Both cyclosporine and tacrolimus increase the risk of PTDM [33]. Tacrolimus is more diabetogenic than cyclosporine [12,13,17,18,23,34-41]. Increased tacrolimus levels have strong associations with impaired glucose tolerance and PTDM. In one study, levels higher than 15 ng/mL were significantly associated with the development of glucose intolerance and PTDM at one year [42]. Incidence rates of PTDM appear to be similar between extended-release versus immediate-release tacrolimus formulations [43].
Both calcineurin inhibitors cause reversible toxicity to islet cells and may directly affect transcriptional regulation of insulin expression [44,45]. Some evidence suggests tacrolimus causes more severe swelling and vacuolization of islet cells [46].
•mTOR inhibitors – Sirolimus is diabetogenic [17,47]. Conversion to sirolimus from tacrolimus or cyclosporine has been associated with a significant worsening of rather than an improvement in 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 calcineurin inhibitor to an mTOR inhibitor [48].
•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) [13]. This benefit may be explained by the use of lower doses of glucocorticoids with these drugs, although this is unproven.
●Preoperative impaired glucose tolerance and perioperative hyperglycemia – Preoperative impaired glucose tolerance identifies transplant candidates who are at higher risk for the development of PTDM. In one study of 120 nondiabetic transplant recipients, an OGTT diagnosed impaired glucose tolerance in 18 percent of patients prior to transplantation [49]. Among 31 patients who developed PTDM, 11 (35 percent) had impaired glucose tolerance pretransplant. Multivariate analysis identified pretransplant impaired glucose tolerance as a risk factor for the development of PTDM (RR 2.4, 95% CI 1.1-5.3). Other studies that have examined the incidence of impaired glucose tolerance and PTDM using serial posttransplant OGTTs suggest that the majority of patients developing persistent PTDM can be identified within three months of transplantation and, conversely, that patients with a normal OGTT 3 to 12 months posttransplant are at low risk for developing late PTDM [16,50].
Perioperative hyperglycemia is also associated with the development of PTDM [17,51]. 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 [51]. By contrast, only 1 of 28 patients (4 percent) who did not have perioperative hyperglycemia developed PTDM. The risk of PTDM was highest among patients who required insulin. Although the incidence and relevance of perioperative hyperglycemia depend upon specific center immunosuppressive protocols (eg, glucocorticoid administration), perioperative hyperglycemia may allow the identification of patients at increased risk for PTDM [51,52].
●Obesity – Several studies have found an association between obesity (body mass index of ≥30 kg/m2) and increased risk of PTDM [13,33,34,36,42,50,53-55].
●Infection – Hepatitis C virus (HCV) infection correlates with both pre- and posttransplant diabetes [13,34-36,56-59]. 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 [58]. Proposed mechanisms for HCV-induced PTDM include HCV-induced islet cell dysfunction and insulin resistance due to liver dysfunction [60]. HCV infection is a potentially modifiable risk factor for PTDM as treatment prior to transplantation may decrease the incidence of PTDM [61].
Cytomegalovirus (CMV) infection has also been reported to increase the risk of PTDM [62,63].
●Hypomagnesemia – Low magnesium levels have been associated with insulin resistance and diabetes in nontransplant patients [64-67]. However, studies evaluating the association between serum magnesium levels and the development of PTDM have shown conflicting results [68-73]. (See "Type 2 diabetes mellitus: Prevalence and risk factors", section on 'Other'.)
Nonmodifiable risk factors — Nonmodifiable risk factors for PTDM include the following [6,13,25,34,50,53,74-76]:
●Increased age (≥40 to 45 years)
●African American race
●Hispanic ethnicity
●History of gestational diabetes or first-degree family history of type 2 diabetes
●Increased human leukocyte antigen (HLA) mismatching
●Male and deceased-donor allografts
Polycystic kidney disease may confer an increased risk of PTDM, although this has not been consistently observed [36,77-82].
Genetic factors — Genetic factors may also contribute to the risk of developing PTDM after kidney transplantation [83-85]. Several different genes have been studied in various populations, but the results of these studies are inconclusive and differ among populations. While the identification of genetic factors that predispose patients to PTDM may aid in deciding the proper immunosuppressive therapy in patients with an increased risk of PTDM, routine genetic testing is not recommended.
EVALUATION AND DIAGNOSIS OF PTDM
Evaluation for PTDM — All kidney transplant recipients, whether or not they have a pre-identified increased risk, should be routinely evaluated for posttransplant diabetes mellitus (PTDM) after transplantation:
●We measure a fasting plasma glucose level weekly during the first four weeks posttransplant after hospital discharge, then at three and six months posttransplant, and then yearly thereafter.
Some centers evaluate for PTDM with an afternoon capillary blood glucose level, rather than a fasting plasma glucose, in the first few weeks posttransplant. This is based on one observational study that showed that afternoon (ie, 4:00 PM) capillary glucose levels ≥200 mg/dL [11.1 mmol/L] were more sensitive than fasting plasma glucose levels, glycated hemoglobin (A1C), and oral glucose tolerance tests (OGTTs) at detecting PTDM within the first six weeks after transplantation (46 versus 0, 4, and 12 percent, respectively) [86]. However, this approach has not yet been validated for the diagnosis of PTDM.
●An A1C can be checked after three months posttransplant, particularly if it is difficult to obtain fasting plasma glucose levels [1,87]. 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.
●We do not routinely perform OGTT to evaluate for PTDM. Although this test is considered the gold standard for the diagnosis of PTDM, its use is limited by inconvenience and cost.
Criteria for the diagnosis of PTDM are presented below. (See 'Establishing the diagnosis' below.)
Establishing the diagnosis — The diagnosis of posttransplant diabetes mellitus (PTDM) should ideally be made when patients are stable on their maintenance immunosuppression regimen, with stable kidney allograft function and in the absence of acute infection [1]. Transient, posttransplant hyperglycemia (see 'Terminology' above) 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, to avoid labeling the majority of kidney transplant recipients with PTDM in the immediate-to-early posttransplant period, a formal diagnosis of PTDM should not be made in patients within the first six weeks after transplantation [1]. However, if the patient fulfills diagnostic criteria for PTDM beyond six weeks posttransplantation, a formal diagnosis of PTDM is made.
PTDM may be diagnosed after transplantation by any of the following, all of which are the same as diagnostic criteria for nontransplant patients:
●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). Fasting is defined as no caloric intake for at least eight hours. An abnormal fasting blood glucose should be confirmed on another day.
●Two-hour plasma glucose ≥200 mg/dL (11.1 mmol/L) during an OGTT. The test should be performed as described by the World Health Organization (WHO), using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.
●A1C ≥6.5 percent, three or more months posttransplant. The A1C is not recommended for diagnosis during the first three months after transplantation [86], because the test may not be valid until new hemoglobin has been synthesized and glycated for the appropriate period in the diabetogenic posttransplant setting [88].
Prediabetes includes impaired fasting glucose and/or impaired glucose tolerance and is diagnosed by a fasting plasma glucose between 100 and 125 mg/dL (5.6 and 6.9 mmol/L) or a two-hour plasma glucose between 140 and 199 mg/dL (7.8 and 11.0 mmol/L) during an OGTT, respectively, according to American Diabetes Association (ADA) guidelines. An A1C of 5.7 to 6.4 percent is also consistent with a prediabetic state [89,90]. Of note, the normal range of fasting plasma glucose differs according to ADA and WHO criteria; an abnormal fasting glucose is defined as ≥100 mg/dL (5.6 mmol/L) by the ADA and ≥110 mg/dL (6.1 mmol/L) by the WHO (see "Clinical presentation, diagnosis, and initial evaluation of diabetes mellitus in adults", section on 'Diagnostic criteria'). Among transplant recipients, the lower threshold advocated by the ADA is more sensitive in identifying patients at risk for PTDM [15].
MANAGEMENT OF HYPERGLYCEMIA IN THE FIRST 6 WEEKS AFTER TRANSPLANTATION
Immediate (<1 week) posttransplantation — Hyperglycemia is very common in the immediate posttransplant period. Since perioperative hyperglycemia is an important risk factor for the development of posttransplantation diabetes mellitus (PTDM), 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 control from the American Diabetes Association (ADA) [91-93]. 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 [94,95]. (See "Management of diabetes mellitus in hospitalized patients", section on 'Insulin infusion'.)
●Noncritically ill patients – When patients are stable and no longer critically ill, we transition from insulin infusion to a subcutaneous insulin regimen. In patients without a previous history of diabetes who require less than 2 units of IV insulin for several (six to eight) hours prior to the transition, the use of correction insulin sliding scale before meals and bedtime (or every six hours if not eating) is generally adequate [96]. Given the heterogeneity of the disease, however, the transition from IV to subcutaneous insulin may need to be individualized, and variables such as glucocorticoid dose and profile, allograft function, concurrent infection, and nutritional source (eg, not eating, enteral or parenteral nutrition) should be considered. 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) [91-93,97].
There are no studies that have specifically compared early insulin therapy with noninsulin agents in the immediate posttransplant setting. However, data from one randomized trial of 50 kidney transplant recipients showed that early basal insulin therapy, compared with short-acting insulin and/or oral hypoglycemic agents, reduced the risk of developing PTDM within the first year after transplant by 73 percent [98]. The authors of this study postulated that early exogenous insulin therapy might protect beta cells from the toxic effects of immunosuppressive therapy and inflammatory stress.
More intensive blood glucose control has not been shown to be beneficial among patients undergoing solid organ transplantation [94,95]. As an example, in one small randomized 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 control, patients in the intensive glycemic control group experienced higher rates of graft rejection, delayed graft function, and hypoglycemia [94].
More details regarding the management of hyperglycemia and diabetes in hospitalized patients are 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 is discussed elsewhere. (See "Anesthesia for kidney transplantation", section on 'Management of hyperglycemia'.)
Early (1 to 6 weeks) posttransplantation — Upon discharge from the hospital, transplant recipients with persistent hyperglycemia, particularly those requiring insulin therapy, should be instructed to perform self-monitoring of blood glucose (SMBG) at home. The optimal frequency of SMBG is not known for this patient population. We suggest initially checking a blood glucose once or twice per day, usually before breakfast (fasting) and again in the afternoon or evening before dinner [86]. Further testing is determined based upon the severity of hyperglycemia and treatment approach. If blood glucose readings are consistently in the normal range, patients can be advised to discontinue SMBG.
There is no high-quality evidence to guide the optimal treatment of hyperglycemia in the early posttransplant period. In addition, the optimal glycemic target in this specific population is not known. We use glycemic targets that are similar to those established by the ADA for nontransplant patients with diabetes (see "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Blood glucose monitoring and target A1C'). Our approach to treatment, which is largely consistent with the recommendations of the 2014 international consensus meeting on PTDM [1], is as follows:
●In most hospitalized patients with hyperglycemia requiring insulin (ie, total daily dose of ≥20 units of insulin) in the immediate posttransplant period (see 'Immediate (<1 week) posttransplantation' above), we continue insulin therapy after hospital discharge. Insulin provides the advantage of easy titration during the first few days after discharge, avoiding the need for urgent visits for hyperglycemic episodes. Many transplant centers have access to diabetes educators or nurse champions with specialized diabetes education training who can train patients on the use of insulin therapy, glucose monitoring, and survival skills.
We typically prefer intermediate-acting neutral protamine hagedorn (NPH) insulin, administered as a single daily dose (initially 5 to 10 units and adjusted based upon the afternoon glucose levels) at the same time as the glucocorticoid dose in the morning [99,100]. The timing of this dose matches the typical afternoon glucose peak that is observed with glucocorticoid-induced hyperglycemia in nondiabetic and diabetic individuals [101]. Alternative options include insulin glargine, administered at night and dose adjusted to control the morning fasting glucose level, or premeal short-acting insulin aspart or insulin lispro, based upon premeal glucose levels and anticipated carbohydrate ingestion. Insulin pump therapy is rarely necessary or indicated in this setting.
The duration of insulin treatment depends upon the patient's response to therapy as well as subsequent blood glucose monitoring. Patients whose insulin requirements decrease to <20 units per day can be transitioned to oral hypoglycemic agents, as discussed below.
●In patients with mild hyperglycemia and low insulin requirements (ie, total daily dose of <20 units of insulin) in the immediate posttransplant period, we treat with oral hypoglycemic agents rather than insulin. We prefer to use agents that have a lower risk of hypoglycemia and have low or no renal excretion, such as meglitinides (eg, repaglinide) or dipeptidyl peptidase 4 (DPP-4) inhibitors (eg, sitagliptin, linagliptin, saxagliptin, alogliptin, vildagliptin). If a meglitinide or DPP-4 inhibitor cannot be used, a sulfonylurea such as glipizide, which has a lower risk of hypoglycemia in patients with kidney impairment, is another option. This is particularly relevant during the early posttransplant period, when patients are experiencing dynamic changes in kidney function and dose adjustments in their immunosuppression regimen. The use of oral hypoglycemic agents to treat posttransplant hyperglycemia is similar to that for patients with established PTDM and is discussed elsewhere in this topic. (See 'Oral hypoglycemic agents' below.)
MANAGEMENT OF PTDM — Most kidney transplant recipients with posttransplant hyperglycemia will experience an improvement of their hyperglycemia once the doses of immunosuppressive agents and glucocorticoids are reduced after transplantation [24]. However, some patients will develop chronic hyperglycemia and may be diagnosed with posttransplantation diabetes mellitus (PTDM) in the late posttransplant setting. (See 'Establishing the diagnosis' above.)
In patients with PTDM or posttransplant prediabetes (ie, impaired fasting glucose or impaired glucose tolerance), we and most experts take a stepwise approach to the management of chronic hyperglycemia [1]. This starts with lifestyle modification, which includes dietary modification, weight reduction, and exercise, and is followed by pharmacologic therapy, first with oral hypoglycemic agents and then with insulin therapy. In kidney transplant recipients with PTDM, the goals of outpatient therapy are to improve glycemic control to lower the risk of microvascular complications and to reduce the risk of cardiovascular disease. (See 'Prognosis' below.)
Lifestyle modification — In all kidney transplant recipients with PTDM, we suggest lifestyle modification interventions focusing on dietary modification, weight reduction, and physical exercise. Lifestyle modification should be attempted prior to the initiation of pharmacologic therapy for PTDM.
Studies examining the effects of lifestyle interventions in the transplant population are limited [102,103]. One trial that randomly assigned 130 nondiabetic kidney transplant recipients to receive active (lifestyle advice delivered by kidney dietitians using behavior change techniques) or passive (lifestyle modification leaflets alone) lifestyle intervention found no significant difference between the groups in insulin secretion, insulin sensitivity, or disposition index after six months of follow-up [102]. However, lifestyle modification may be beneficial based upon data in nontransplant patients with type 2 diabetes mellitus. These issues are discussed in more detail elsewhere:
●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus", section on 'Exercise'.)
Pharmacologic therapy — Pharmacologic therapy for PTDM should begin with oral hypoglycemic agents. If adequate glycemic control cannot be achieved with oral agents, patients can be started on insulin therapy.
Oral hypoglycemic agents — There is insufficient evidence to support a first-line agent for the chronic management of hyperglycemia in PTDM [2,104,105]. Drug selection should consider efficacy, side effects, potential drug-drug interactions, and cost.
In general, we start oral treatment with sulfonylureas, meglitinides, or DPP-4 inhibitors, although data demonstrating their safety and efficacy in kidney transplant recipients with PTDM are limited. We tend not to use metformin, given the potential (but rare) risk for lactic acidosis in the setting of kidney function impairment. We do not routinely use glucagon-like peptide (GLP) 1 agonists, alpha-glucosidase inhibitors, or sodium-glucose co-transporter 2 (SGLT2) inhibitors as first-line oral agents; however, these agents may be considered in patients who require additional therapy or who do not tolerate initial oral therapy. Emerging data suggest that SGLT2 inhibitors may be associated with benefits beyond glycemic control in kidney transplant recipients. Thiazolidinediones are generally not used among transplant recipients.
The following discussion of oral therapy emphasizes those aspects specific to kidney transplant recipients. General discussions of the use of these agents are presented in separate topic reviews.
●Sulfonylureas – Among the sulfonylureas, glipizide and glimepiride are preferred to glyburide when the estimated glomerular filtration rate (eGFR) is less than 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 maintain the glycated hemoglobin (A1C) level at less than 7 percent. Less than 5 percent of glipizide is renally excreted and does not change levels of cyclosporine in kidney transplant recipients [2]. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Sulfonylureas'.)
●Meglitinides – Meglitinides, such as repaglinide, have been shown to be effective in some PTDM patients. 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 [106]. However, a higher cost than sulfonylureas and two- or three-times daily dosing may be a limitation. (See "Sulfonylureas and meglitinides in the treatment of type 2 diabetes mellitus", section on 'Meglitinides'.)
●Dipeptidyl peptidase 4 (DPP-4) inhibitors – DPP-4 inhibitors (sitagliptin, linagliptin, saxagliptin, alogliptin, vildagliptin) cause a glucose-dependent increase in insulin release. Limited data suggest that DPP-4 inhibitors are generally safe and effective in kidney transplant recipients. (See "Dipeptidyl peptidase 4 (DPP-4) inhibitors for the treatment of type 2 diabetes mellitus".)
With the exception of linagliptin, which is primarily eliminated via the enterohepatic system, all DPP-4 inhibitors are mainly cleared by the kidneys and require dose reduction in patients with moderate to severe kidney impairment. In general, DPP-4 inhibitors do not have any significant drug interactions with maintenance immunosuppressive agents, with the possible exception of sitagliptin, which may cause an increase in cyclosporine trough levels [107,108]. The use of these agents may be limited by their high cost.
Only sitagliptin, linagliptin, and vildagliptin have been evaluated in kidney transplant recipients [107,109-112]. 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 [109,110,112]. Although sitagliptin does not cause hypoglycemia, it may prolong the QT interval, especially if used with cyclosporine. A randomized controlled trial of vildagliptin versus placebo in 33 stable kidney transplant recipients with PTDM identified by oral glucose tolerance test (OGTT) demonstrated significant improvement in OGTT-derived two-hour plasma glucose (183 versus 231 mg/dL) and A1C (6.1 versus 6.5 percent) after three months of treatment with similar and mild adverse events between groups [111].
Whether any specific DPP-4 inhibitor is more effective or easier to use in kidney transplant recipients is unclear. In a retrospective study from Korea that compared the glucose-lowering efficacies of different DPP-4 inhibitors in kidney transplant patients with diabetes, a greater decrease in A1C was observed in patients treated with linagliptin compared with those treated with vildagliptin or sitagliptin (-1.40 versus -0.38 and -0.53 percent, respectively) [107]. Cyclosporine trough levels were significantly increased among patients treated with sitagliptin compared with those treated with vildagliptin but were minimally changed in those treated with linagliptin.
●Metformin – We generally do not use metformin, because kidney function impairment increases the risk of lactic acidosis with this agent. However, this is considered to be a rare event [113], and the 2016 changes in labeling of metformin allow initiation of metformin in patients with an eGFR as low as 45 mL/min/1.73 m2. In the United States, it is strictly contraindicated in patients with an eGFR of <30 mL/min/1.73 m2 and not recommended if the eGFR is between 30 and 45 mL/min/1.73 m2. Some experts advocate for metformin based upon data from observational studies and one small randomized trial of patients with impaired glucose tolerance that have shown favorable patient and graft outcomes as well as safety and efficacy [114-116]. (See "Metformin in the treatment of adults with type 2 diabetes mellitus".)
●Glucagon-like peptide (GLP) 1 receptor agonists – GLP-1 receptor agonists (liraglutide, exenatide, dulaglutide, semaglutide, lixisenatide) improve glycemic control by enhancing glucose-dependent insulin secretion, delaying gastric emptying, regulating postprandial glucagon, and reducing food intake. We do not routinely use GLP-1 receptor agonists as initial oral pharmacologic therapy in kidney transplant recipients with PTDM given the limited evidence for their use in this patient population. 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 [117]. 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. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)
●Alpha-glucosidase inhibitors – Alpha-glucosidase inhibitors such as acarbose or miglitol are not considered first- or second-line agents but may be considered if other options are not available. Alpha-glucosidase inhibitors slow carbohydrate absorption and reduce postprandial blood-sugar peaks. They are relatively less effective in lowering glycemia, compared with other antidiabetic medications, but do not cause weight gain. These agents are relatively inexpensive, but their use may be limited by common gastrointestinal side effects, particularly in the setting of mycophenolate mofetil (MMF) treatment. There is a reduced risk of hypoglycemia [118]. (See "Alpha-glucosidase inhibitors for treatment of diabetes mellitus", section on 'General approach'.)
●Thiazolidinediones – Thiazolidinediones are generally not used among transplant recipients, unless there are no other alternatives. We do not use rosiglitazone in any transplant recipient. The thiazolidinediones may worsen immunosuppression-associated bone loss and are commonly associated with formation of edema, which may necessitate the use of diuretics and may predispose to calcineurin toxicity. Use of these agents is also contraindicated in hepatic dysfunction. (See "Thiazolidinediones in the treatment of type 2 diabetes mellitus".)
●Sodium-glucose co-transporter 2 (SGLT2) inhibitors – SGLT2 inhibitors (dapagliflozin, canagliflozin, empagliflozin) inhibit glucose absorption in the proximal tubule, causing glucosuria, weight loss, and improved glycemic control [119]. In nontransplant patients with chronic kidney disease (CKD), the use of SGLT2 inhibitors has been shown to lower the risk of kidney failure and cardiovascular events [120]. (See "Sodium-glucose cotransporter 2 inhibitors for the treatment of hyperglycemia in type 2 diabetes mellitus".)
We do not recommend the routine use of SGLT2 inhibitors in kidney transplant recipients with PTDM at this time, given the limited efficacy and safety data in this patient population. However, some clinicians may treat PTDM with SGLT2 inhibitors on a case by case basis. Because these agents cause glucosuria, there is an increased incidence of urinary tract infections, which already have an increased incidence in kidney transplant recipients. These drugs appear to have minimal drug-drug interactions with common immunosuppressants, with the possible exception of mammalian (mechanistic) target of rapamycin (mTOR) inhibitors [108].
Data examining the safety and efficacy of SGLT2 inhibitors in kidney transplant recipients with PTDM are limited but increasing [121-125]. In one small trial that randomly assigned 44 kidney transplant recipients with PTDM to empagliflozin (10 mg daily) or placebo for 24 weeks, treatment with empagliflozin produced a greater decrease in A1C compared with placebo (-0.2 versus 0.1 percent, respectively) [121]. However, the magnitude of this reduction was limited and dependent upon eGFR and baseline A1C. At 24 weeks, there were no differences between the groups in adverse events, immunosuppressive drug levels, or eGFR. Another small case series of 10 patients treated with canagliflozin reported modest reductions in A1C over a mean of 10 months of follow-up, without any urinary or mycotic infections [122].
Observational studies suggest that the use of SGLT2 inhibitors in kidney transplant recipients with PTDM may be associated with benefits beyond glycemic control [125-127]. 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) [125]. 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 [126].
Insulin therapy — Many patients will require initiation of insulin, especially those with blood sugars above 200 mg/dL (11.1 mmol/L). We initiate insulin therapy if oral agents have not been effective or have been accompanied by unacceptable side effects, or if A1C levels are consistently above 7 percent.
Diurnal glucose patterns differ among patients who are receiving glucocorticoids, compared with those who are not. Thus, even with small doses of glucocorticoids of 5 mg per day in the morning, we have typically observed a late-afternoon or early-evening peak in blood glucose concentration that is often much higher than the fasting blood-glucose concentrations.
There are little data regarding insulin therapy among patients who are receiving glucocorticoids.
A detailed discussion of insulin therapy is available in separate topic reviews:
●(See "Insulin therapy in type 2 diabetes mellitus".)
●(See "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)
●(See "Management of blood glucose in adults with type 1 diabetes mellitus".)
Adjustment of immunosuppression — Adjustment of immunosuppression therapy aimed at improving glucose tolerance may be considered among patients with PTDM. 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.
●Glucocorticoids – The glucocorticoid dose should be decreased as soon as possible, but complete glucocorticoid withdrawal is not recommended [6]. Prednisolone dose reduction to 5 mg/day at one year has been associated with a decrease in glucose intolerance from 55 to 34 percent [27]. Although complete glucocorticoid withdrawal can reduce the incidence of PTDM, a significant percentage of patients suffer a rejection episode requiring reinstitution of glucocorticoid therapy [128]. One study also found no improvement in insulin sensitivity when dropping from 5 mg to complete prednisolone withdrawal [30]. Though not well studied in transplant recipients, divided dosing may reduce variability and peak of glucocorticoid-induced hyperglycemia [129].
●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 (see 'Modifiable risk factors' above). Thus, in affected patients, consideration should be given to reducing the tacrolimus dose.
We generally do not switch patients with PTDM from tacrolimus to cyclosporine, unless there are other tacrolimus-related side effects, since the effect of tacrolimus on glucose tolerance may be reversible even if the agent is not discontinued. In one study, for example, 70 percent of White patients and 20 percent of African American patients were able to discontinue insulin without discontinuing tacrolimus or glucocorticoids [130]. In addition, one large review reported an improved graft survival with tacrolimus therapy despite the increased rate of PTDM seen with tacrolimus and the association of PTDM with decreased graft survival [13]. Another registry analysis of the United States Renal Data System (USRDS) database of nearly 50,000 patients transplanted between January 1998 and December 2002 (during which time tacrolimus and cyclosporine had equal market share) showed that diabetes was associated with worse patient and graft survival but no differences based on whether tacrolimus or cyclosporine was used despite a higher incidence of PTDM among those who received tacrolimus [131].
However, some studies suggest that switching from tacrolimus to cyclosporine may improve glucose control and return normal glucose tolerance. A small trial randomly assigned 67 kidney transplant recipients with PTDM to cyclosporine conversion versus tacrolimus continuation and demonstrated a significant improvement in A1C in the cyclosporine arm and reversal of PTDM [132]. Another randomized trial showed the benefit of switching tacrolimus to cyclosporine in recipients who developed PTDM, with 34 percent of subjects in the cyclosporine conversion group versus 10 percent in the tacrolimus continuation group resolving their PTDM [133]. Thus, switching to cyclosporine may be considered among patients in whom diabetes remains difficult to control on lower-dose tacrolimus [6].
Conversion to mTOR inhibitors (sirolimus, everolimus) is not recommended to reduce the risk of or reverse PTDM. Sirolimus may worsen insulin resistance and glycemia [48,134].
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 may experience an improvement in glucose control [135].
Monitoring — In kidney transplant recipients with PTDM, an A1C should be checked every three months. The optimal glycemic target for kidney transplant recipients with PTDM is not known. In general, the goals for glycemic control 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, the 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 [136]. (See "Glycemic control 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 being used. Patients should be instructed in glucose self-monitoring. Patients should have regular screening for retinopathy and neuropathy. Regular foot care is also indicated.
PROGNOSIS
●Patient survival – The development of posttransplantation diabetes mellitus (PTDM) has an adverse effect upon patient survival in most studies [13,32,53,54,137-146]:
•In one study, one-year patient survival was 83 and 98 percent in those with and without PTDM, respectively [53]. A subsequent report found that five-year survival with PTDM was 87 versus 93 percent among nondiabetic patients [76]. 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 [147]. 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 [13,148-153]. 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 [13,149,151]. Some of the excess risk is associated with coexistence of other cardiovascular risk factors, particularly increased age and dyslipidemia [151].
The effect of new-onset PTDM on cardiovascular or overall mortality may not be as great as the adverse effects of pretransplant diabetes on mortality, at least at 1.5 years. This was suggested by a large cohort study that examined outcomes of 37,448 recipients who had survived for longer than one year with a functioning transplant [154]. Recipients were stratified according to the absence or presence of diabetes and occurrence of acute rejection at one year following transplant. At a median follow-up of 1.5 years, pretransplant diabetes, but not new-onset diabetes, was associated with higher all-cause and cardiovascular mortality. This study is limited by the short duration of follow-up; 1.5 years may not be sufficient to show an adverse effect of new-onset diabetes [155].
●Allograft survival – Most, but not all, studies have shown that PTDM decreases long-term allograft survival. In one study, for example, graft survival at 12 years was 48 and 70 percent in those with and without PTDM, respectively [156]; this was associated with a RR of loss of 3.72.
Most, if not all, of the adverse effect on allograft survival is due to the increase in mortality associated with PTDM. As an example, in a retrospective analysis of 27,707 transplant recipients, PTDM was associated with increased risk for allograft failure from any cause but not for death-censored graft loss (or graft loss without death) [142]. However, another large, retrospective study suggested that PTDM was associated with increased risk for both overall allograft failure and for death-censored allograft failure [13]. Unlike the study cited above, however [142], this study did not control for acute rejection in the multivariate analysis.
The mechanism by which PTDM may decrease allograft survival independent of increased mortality is not clear. Some have suggested that the occurrence of diabetic nephropathy may contribute to the increased rate of graft failure without death [157]. Another possibility is that efforts to decrease diabetogenic immunosuppressive therapy in order to prevent PTDM and its complications may increase rates of rejection [156].
However, the effect of diabetes on death-censored allograft loss is less than that of acute rejection. This was demonstrated in the study cited above that showed that acute rejection, but not diabetes, was associated with higher death-censored transplant failure at a median follow-up of 1.5 years [154]. Although limited by the short follow-up time, this large study suggests that acute rejection is the most significant potentially modifiable factor in allograft survival and underlines the importance of maintaining adequate immunosuppression to prevent rejection, even at the expense of the development of new-onset diabetes [155].
●Infections – PTDM has been associated with an increased risk for infection and sepsis, with hyperglycemia possibly altering the immune response [53,76,141,156,158]. Urinary tract infection, pneumonia, and cytomegalovirus (CMV) have also been reported to occur at increased rates with diabetes [53,76,141].
●Diabetic 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 [159]. Ophthalmic and neurologic complications occurred in 8 and 16 percent of patients, respectively [159]. 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 [159]. (See 'Modifiable 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
●Overview – Diabetes occurs in a moderate fraction (approximately 20 percent) of patients following kidney transplantation. Posttransplantation diabetes mellitus (PTDM) is associated with increased mortality and morbidity and, in particular, higher rates of kidney transplant rejection, cardiovascular disease, and infection, which are the leading causes of death in kidney transplant recipients. (See 'Introduction' above and 'Prognosis' above.)
●Risk factors – Several modifiable and nonmodifiable factors may increase the risk for PTDM among kidney transplant recipients, including immunosuppressive agents, preoperative impaired glucose tolerance and perioperative hyperglycemia, obesity, infection, and hypomagnesemia. (See 'Risk factors' above.)
●Evaluation and diagnosis – All kidney transplant recipients, whether or not they have a pre-identified increased risk, should be routinely evaluated for and informed about the risk of PTDM after transplantation. The diagnosis of PTDM should ideally be made when patients are stable on their maintenance immunosuppression regimen, with stable kidney allograft function and in the absence of acute infection. Transient posttransplant hyperglycemia is very common in the immediate-to-early posttransplant period but usually resolves within the first few weeks after transplantation. Thus, to avoid labeling the majority of kidney transplant recipients with PTDM in the immediate-to-early posttransplant period, a formal diagnosis of PTDM should not be made in patients within the first six weeks after transplantation. PTDM may be diagnosed after transplantation based upon diagnostic criteria similar to those used in the nontransplant population. (See 'Evaluation and diagnosis of PTDM' above.)
●Management of hyperglycemia in the early posttransplant period – Our approach to the management of hyperglycemia in the first six weeks after transplantation is as follows:
•Immediate (<1 week) posttransplantation – In the immediate postoperative period, blood glucose levels should be routinely monitored, and patients with hyperglycemia (plasma glucose ≥180 mg/dL [10.0 mmol/L]) should be treated with insulin therapy using a standard intravenous (IV) insulin infusion protocol. When patients are stable and no longer critically ill, we transition from insulin infusion to a subcutaneous insulin regimen. (See 'Immediate (<1 week) posttransplantation' above.)
•Early (1 to 6 weeks) posttransplantation – Upon discharge from the hospital, transplant recipients with persistent hyperglycemia, particularly those requiring insulin therapy, should be instructed to perform self-monitoring of blood glucose (SMBG) at home. In most hospitalized patients with hyperglycemia requiring insulin (ie, total daily dose of ≥20 units of insulin) in the immediate posttransplant period, we continue insulin therapy after hospital discharge. In patients with mild hyperglycemia and low insulin requirements (ie, total daily dose of <20 units of insulin) in the immediate posttransplant period, we treat with oral hypoglycemic agents rather than insulin. (See 'Early (1 to 6 weeks) posttransplantation' above.)
●Management of PTDM – In patients with established PTDM or with prediabetes (impaired fasting glucose or impaired glucose tolerance), we and most experts take a stepwise approach to the management of chronic hyperglycemia. This starts with lifestyle modification, which includes dietary modification, weight reduction, and exercise, and is followed by pharmacologic therapy, first with oral hypoglycemic agents and then with insulin therapy. Adjustment of immunosuppression therapy aimed at improving glucose tolerance may be considered among patients with PTDM. However, the potential benefit of altering immunosuppressive agents must be weighed against the risk of allograft rejection. (See 'Management of PTDM' above.)
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