Diabetes mellitus in transplantation: 2002 consensus guidelines

Diabetes Mellitus in Transplantation: 2002 Consensus Guidelines R. Moore, A. Boucher, J. Carter, S.J. Kim, B. Kiberd, R. Loertscher, J.G. Mongeau, G.V.R. Prasad, L. Vautour, and the Posttransplant Diabetes Mellitus Advisory Board ABSTRACT Diabetes mellitus is a serious complication following organ transplantation that is underdiagnosed, possibly due to the inadequate definitions used in published literature and the lack of standardized screening. Diabetes in transplantation amplifies the already increased risk of cardiovascular disease among transplant patients, and increases the risk of graft loss and death. Patients at risk of developing diabetes in transplantation should therefore be prospectively identified and given individualized immunosuppressive therapy to minimize the risk of developing this disease. These guidelines are intended to: (1) help identify patients at risk for diabetes after transplantation; (2) set down a standard definition of posttransplant diabetes mellitus (PTDM); (3) create a standard monitoring protocol for the diagnosis of PTDM; and (4) optimize the management of patients at risk of developing or who develop diabetes after transplantation. With improved diagnosis, individualization of therapy, and proper early management, the incidence of diabetes in transplantation, and the accompanying additional burden of illness the disease carries, may be diminished. In turn, this will help achieve the therapeutic goals of reducing the risk of graft complications, improving quality of life, and reducing postoperative morbidity and mortality in transplant patients.

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HE WORLD HEALTH ORGANIZATION (WHO), defines diabetes mellitus (DM) as a “metabolic disorder of multiple aetiology characterised by chronic hyperglycaemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both.”1 In recent years, the incidence of diabetes in the overall population has been steadily rising, making it a leading public health problem. According to the Diabetes Screening in Canada (DIASCAN) study, the prevalence of type 2 diabetes in Canadians ⬎40 of age who see a general practitioner is 16.4%.2 Its incidence increases with age, increasing from 8.2% in people aged ⱖ20 years to 18.4% in people ⱖ65 years.3 Type 1 diabetes is generally the result of beta-cell destruction, and requires insulin therapy. Type 2 diabetes appears to be the result of a combination of insulin resistance and insulin deficiency. Although the two types of diabetes differ in their pathophysiology, the long-term consequences are the same.4 Diabetes is associated with several microvascular complications, including neuropathy, nephropathy, and retinopathy, as well as macrovascular complications such as myo© 2003 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35, 1265-1270 (2003)

cardial infarction, stroke, and peripheral vascular disease.3 Diabetes is an independent risk factor for cardiovascular disease (CVD). It is now generally accepted that the presence of diabetes confers equivalent risk to a cardiovascular event.5 In addition, age-specific mortality rates increase two- to fourfold in patients with diabetes. DIABETES IN TRANSPLANTATION

An increasing number of patients have diabetes prior to their transplant,3 or develop diabetes afterwards. It is clear that diabetes places an additional burden on transplant patients and threatens the outcome of transplantation.6 Clinical studies have suggested that posttransplant diabetes mellitus (PTDM) is associated with lower overall patient From The Post-Transplant Diabetes Mellitus Advisory Board Meeting in Montreal, Quebec, Canada, on June 15, 2002. This Advisory Board was made possible by an unrestricted grant from Novartis Pharmaceuticals Canada, Inc. The opinions expressed in this issue do not necessarily reflect those of the sponsor. Address reprint requests to Dr R. Moore, University Hospital of Wales, Consultant Neurologist, Clinical Director of Nephrology and Transplantation, Cardiff, Wales, UK. 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00434-2 1265

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survival, and increased graft loss, as well as higher mortality associated with graft loss, chronic heart disease (CHD), and stroke.7 In addition, diabetes in transplantation amplifies the cardiovascular risk, which is already high among transplant patients. Also, given the metabolic similarities of PTDM with idiopathic diabetes, it is assumed that PTDM carries the same risk of long-term complications as type 1 or type 2 diabetes in the general population.6,8 Posttransplant diabetes is believed to be multifactorial, probably involving beta-cell toxicity and increased insulin resistance.9 –11 Steroids impair glucose metabolism mainly by inducing insulin resistance and increasing hepatic gluconeogenesis. While potentiating the hyperglycemic effects of corticosteroids, calcineurin inhibitors have a more complex mechanism of action, which may include islet toxicity, diminished insulin synthesis or release, and decreased peripheral insulin sensitivity.7 It also appears that PTDM is more frequently associated with the use of tacrolimus than with cyclosporine.12 Most cases of PTDM develop within 1 year of kidney or liver transplantation; however, new cases have been reported for up to 5 years posttransplantation.13 In studies where PTDM was defined by fasting blood glucose (FBG) concentrations, its incidence in renal transplantation has been as high as 20%;14 however, incidence has ranged from about 2.5% to 25%, depending on the definition of PTDM used. PTDM is also known to occur in children, although at a lower incidence of 1% to 2.6%.15 In liver transplantation, the range is from about 2% to 33%. In one of the largest studies, involving 1000 consecutive patients treated with tacrolimus, a 24% prevalence of insulin-dependent diabetes was reported at 3 months posttransplant, which had decreased to 18% at 5 years.13 Relatively few trials have reported the risk of developing PTDM in other organ transplantation, but early evidence seems to point to a similar incidence.13 Differing definitions of diabetes and PTDM make it difficult to determine the incidence of the disease. Furthermore, methodologic inconsistencies between studies that were generally not designed to detect diabetes in transplantation have also contributed to inaccurate estimates of the frequency of this problem. In 1998, the Canadian Clinical Guidelines for the Management of Diabetes in Canada were revised. Among the revisions were changes to the diagnostic criteria, and the introduction of intermediate stages of abnormal glucose homeostasis as follows: ● The specific fasting plasma glucose (FPG) level to diagnose diabetes was reduced from 7.8 to 7.0 mmol/L. ● The term impaired fasting glucose (IFG) was established to identify the intermediate stage of abnormal glucose homeostasis between 6.1 and 6.9 mmol/L. ● Impaired glucose tolerance (IGT) was defined as a plasma glucose level of between 7.8 and 11.0 mmol/L at 2 hours after a 75-g glucose load (2hPG).

MOORE, BOUCHER, CARTER, ET AL Table 1. Diagnosis of Diabetes* Diagnosis of diabetes should include symptoms of diabetes plus a: ● Casual glucose value of ⱖ11.1 mmol/L OR ● Fasting plasma glucose (FPG) ⱖ7.0 mmol/L OR ● Plasma glucose value of ⱖ11.1 mmol/L 2 hours after a 75-g glucose load (2hPG) A confirmatory laboratory test based on measurements of venous plasma glucose must be done on another day in the absence of unequivocal hyperglycemia accompanied by acute metabolic decompensation. *Source: Clinical Practice Guidelines for the Management of Diabetes in Canada, Canadian Diabetes Association.

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Patients presenting with IFG or IGT should be monitored annually for the development of diabetes, and risk factors and lifestyle factors should be addressed.

CONSENSUS GUIDELINES DEFINITION OF POSTTRANSPLANT DIABETES MELLITUS

Definitions applied to PTDM in the past have been both inconsistent and/or inappropriate. The commonly used definition in clinical trials is the requirement of insulin for a minimum period (usually 30 days) posttransplantation. This definition has resulted in an underestimate of the prevalence of diabetes in transplantation, because it excludes patients treated with oral antidiabetic agents, as well as those with asymptomatic hyperglycemia and IGT. In addition, these earlier definitions of PTDM did not distinguish between patients with new-onset diabetes after transplantation from those with worsening of disease. The first step toward developing consensus guidelines for the definition and diagnosis of PTDM is to apply the generally accepted Canadian Diabetes Association and World Health Organization definitions of diabetes mellitus to PTDM. These guidelines take into account the current understanding that IGT and IFG are both important risk factors that contribute to the development of diabetes. Recommendation

The definition of PTDM should be based on the currently accepted definition of diabetes, as defined by the Canadian Diabetes Association and clinical practice guidelines for the identification and management of diabetes. The current diagnostic criteria are presented in Tables 1 and 2. These criteria are based on venous sample methods in the laboratory. IFG is defined as a fasting plasma glucose between 6.1 and 6.9 mmol/L. IFG and IGT are associated with an increased risk for the development of diabetes, and therefore these patients should also be closely monitored posttransplant. Similarly to gestational diabetes, transient diabetes is defined as the need for hypoglycemic treatment for ⬍30 days or elevated plasma glucose values (Table 1) that resolve within 30 days. A patient who has had transient diabetes at any stage is at high risk and should be monitored carefully to minimize further risk.

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Table 2. Glucose Levels for Diagnosis in Nonpregnant Adults*

Category

Impaired fasting glucose (IFG) Impaired glucose tolerance (IGT) Diabetes mellitus (DM)

Plasma glucose 2 hours after 75-g Fasting plasma glucose load (2hPG) glucose (mmol/L) (mmol/L)

6.1– 6.9 ⬍7.0 ⱖ7.0

NA 7.8 –11.0 ⱖ11.1

NA, not applicable. *Source: Clinical Practice Guidelines for the Management of Diabetes in Canada, Canadian Diabetes Association.

A transiently diabetic patient is confirmed as having new-onset diabetes if hypoglycemic treatment needs to be continued for ⬎30 days or if two plasma glucose tests at timepoints ⬎30 days apart confirm elevated values, as described in Table 1. BASELINE EVALUATION Before Initiating Immunosuppressant Therapy

Clinical examination. During the initial consultation for transplantation eligibility, the patient’s complete medical history should be documented, and potential risk factors for diabetes in transplantation should be identified. There is growing evidence that diabetes in transplantation is associated with certain risk factors, which are probably important for all organ transplants. Prospective identification of risk factors and individualization of immunosuppressive therapy may help reduce the risk of diabetes after transplantation and is therefore an important step in clinical assessment and management of patients.

increase the risk of developing PTDM in renal transplantation, as does treatment with tacrolimus in older children (14 versus 8.2 years of age). Conversely, age does not appear to be a factor in liver transplantation. Other possible factors with limited or conflicting evidence include body mass index (BMI), waist– hip ratio, and concurrent treatment with beta-blockers. Gender does not appear to be a contributory factor (Fig 1).13 SCREENING AND MONITORING Pretransplant

During initial consultation for transplantation, the following assessments should be made: ● Documentation of complete medical history. ● Documentation of glucose history (fasting blood glucose value). ● Determination of risk factors for PTDM, including: African, Asian, or Hispanic descent. Family history of DM. History of gestational diabetes. Other risk factors for developing diabetes (ie, obesity, markers of Metabolic syndrome, or insulin resistance). Advanced age (⬎45 years is associated with a twofold increased risk; ⬎63 years with a threefold increase). Posttransplant ●

Risk Factors

There are no clearly established risk factors for the induction of PTDM in individual patients. One or more different mechanisms may occur in patients susceptible to diabetes. However, several characteristics appear to predispose patients to the development of PTDM. Family history. In some studies, family history has been identified as a risk factor for the development of PTDM. As an example of genetic predisposition, HLA-B27 status was found to be associated with a fivefold increased risk of PTDM.13 Ethnicity. There is strong evidence that individuals of African or Hispanic descent are more likely than whites to develop PTDM.13 Both these populations were observed to have a threefold increased risk of PTDM at 1 year in a study of outcomes by the US FK 506 Kidney Transplant Study. The United States Food and Drug Administration (FDA) subsequently noted that tacrolimus was associated with a fivefold greater overall risk than cyclosporine, and that this effect was magnified in nonwhite patients who were already at increased risk of PTDM.13 There was anecdotal evidence among panel participants that the Asian and Philippine populations are also at increased risk for developing diabetes after transplantation when treated with tacrolimus. Other factors. Advanced age (⬎45 years) appears to

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Fasting plasma glucose should be monitored regularly: At least once a week for the first 4 weeks posttransplant. At 3 months posttransplant. At 6 months posttransplant. Annually posttransplant. Plasma glucose levels should also be randomly monitored at regular intervals, ideally when patients present for blood monitoring of plasma immunosuppressant levels. Oral glucose tolerance tests (OGTT; plasma glucose at 2 hours after a 75-g glucose load) may be performed at the physician’s discretion.

Note. PTDM may occasionally resolve with time in some patients, especially in children.18 However, like gestational diabetes, the patient should be considered at increased risk for the development of type 2 diabetes at a later time. Therefore, FPG should be monitored regularly for all patients, regardless of current or previous PTDM status. Close attention should be paid to patients who have previously been diagnosed with diabetes, and lifestyle choices should be strongly reinforced. In these patients, IGT and abnormal lipid profiles should lead to the implementation of intensive prevention strategies (Fig 2). MANAGEMENT AND INDIVIDUALIZATION OF THERAPY

There is evidence that not all immunosuppressant therapies are equivalent in their potential to cause diabetes after

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Table 3. Immunosuppressive Agents and Cardiovascular Disease Drug

Blood pressure

Lipids

Diabetes

Acute rejection

Prednisone Cyclosporine Tacrolimus RAP MMF Anti-CD25 MAb

⫹⫹ ⫹⫹⫹ ⫹⫹⫹ ⫾ ⫾ ⫾

⫹⫹ ⫹⫹ ⫹ ⫹⫹⫹ ⫾ ⫾

⫹⫹⫹ ⫹ ⫹⫹ ⫾ ⫾ ⫾

⫺ ⫺⫺ ⫺⫺ ⫺⫺⫺ ⫺⫺⫺ ⫺⫺⫺

Adapted from Jardine.16

transplantation (Table 3). Immunosuppressive therapy should therefore be individualized, based on risk factors, prior to transplantation. Immunosuppressive therapy. The relationship between treatment with steroids and diabetes after transplantation has been fairly clearly established. Studies that use oral glucose tolerance tests (OGTT) have clearly demonstrated that steroid dose is associated with both PTDM and impaired glucose tolerance after renal transplantation. Incremental increases of 0.01 mg/kg per day of prednisone appear to be associated with a 5% increase in risk of developing PTDM. In addition, 1-mg/d reductions in prednisone dosage have been associated with decreases of 0.12 mmol/L in 2-hour serum glucose concentrations.15 Tacrolimus may also be associated with an increased incidence of PTDM. In the European FK 506 Liver Study, patients treated with tacrolimus experienced a higher incidence of PTDM than those treated with cyclosporine, despite significantly lower doses of corticosteroid to treat acute rejection.13 In pediatric renal graft recipients, tacrolimus has consistently been found to be associated with a higher risk of diabetes than cyclosporine. In one study, impaired glucose tolerance was found to be related to tacrolimus dose.13 Cyclosporine has also been associated with PTDM, but apparently to a lesser degree than tacrolimus.13 It is believed that calcineurin inhibitors contribute to PTDM through mechanisms such as islet toxicity, diminished insulin synthesis or release, and decreased peripheral insulin sensitivity, in addition to potentiating hyperglycemic effects of corticosteroids.7 Azathioprine dosage and the use of additional immunosuppressants, such as antilymphocyte globulin and OKT3, have not been associated with PTDM.13 Pretransplant Recommendations

All patients should be counseled on the importance of weight control, healthy diet, and physical activity to help prevent diabetes. With those at increased risk for diabetes after transplantation, recommendations are particularly important and should be reinforced whenever possible. In addition, individual therapy should be tailored and patients monitored closely: ● Avoid steroids, or taper steroids very rapidly. ● Administer cyclosporine (Neoral) as the preferred calcineurin inhibitor.

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Consider adjunct treatment with anti-CD25 antibody, to allow steroid avoidance or rapid elimination.

Recommended Management of Posttransplant Diabetes

PTDM diagnoses do not differ from those for the general population, as put forth in the Canadian Clinical Guidelines. Potential markers for diabetes, such as impaired fasting glucose and impaired glucose tolerance, should also be considered, and managed in accordance with the Canadian Clinical Guidelines. The glucose levels for the diagnosis of these conditions are listed in Table 2. Potentially Transient Diabetes After Transplantation ● Importance of weight control, healthy diet, and physical activity should be reinforced. ● Taper steroids as rapidly as possible. Persistent Diabetes After Transplantation Consider switching patient to cyclosporine (Neoral) if on tacrolimus. ● Follow Canadian Diabetes Association (CDA) guidelines for the treatment of type 2 diabetes. ●

GUIDELINES FOR MANAGEMENT OF DIABETES IN TRANSPLANTATION

Management of PTDM should be based on the most current clinical practice guidelines from the CDA. The following outlines the recommended treatment strategies for type 2 diabetes as put forth in the 1998 guidelines. There is strong evidence that, in diabetes, decreasing the blood glucose levels close to normal range reduces the frequency of microvascular complications and that improving lipid levels reduces the frequency of coronary artery disease (CAD). Target glucose levels are given in Table 4. “Ideal levels” are levels within the normal range for people without diabetes. “Optimal levels” are those that approach the normal range and are associated with a low risk of developing long-term complications of diabetes. “Suboptimal levels” are attainable for most patients. However, patients and their caregivers should still strive to lower glucose levels further. “Inadequate levels” are associated with acute symptoms of hyperglycemia and a marked increased risk of long-term complications. Table 5 shows the target lipid levels for the prevention of CAD in individuals with diabetes. It acknowledges the fact that diabetes is a potent risk factor for both men and women after the age of 30 years. Monitoring Recommendations for Patients With PTDM ●

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Glycated hemoglobin (HbA1c) should be measured every 3 to 4 months in all patients taking insulin and at least every 6 months in patients on nutritional therapy or oral hypoglycemic agents. Self-monitoring of blood glucose is an essential component of the therapeutic plan of patients taking insulin therapy.

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Table 4. Levels of Glucose Control for Adults and Adolescents With Diabetes Mellitus Level

Glycated Hb Percent of upper limit HbA1C assay Fasting or premeal glucose level (mmol/L) Glucose level 1–2 h after meal (mmol/L)

Ideal (normal nondiabetic)

Optimal (target goal)

Suboptimal (action may be required)

Inadequate (action required)

ⱕ100 0.04 – 0.06 3.8 – 6.1 4.4 –7

ⱕ115 ⬍0.07 4 –7 5.0 –11

116 –140 0.07– 0.084 7.1–10 11.1–14

⬎140 ⬎0.084 ⬎10 ⬎14

Hb, hemoglobin.

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Self-monitoring of blood glucose is an integral component of the therapeutic plan of patients taking oral hypoglycemics, and may be useful for patients on diet therapy alone. To ensure optimal self-monitoring of blood glucose, the patient should be educated on the proper use of a glucose meter, interpretation of results, and how to modify treatment based on results.

Stepwise Management Approach to Diabetes in Transplantation ●

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Rigorous lifestyle counseling and oral hypoglycemic agents should be initiated as the first steps in the treatment of persistent PTDM. All patients can benefit from home glucose monitoring. This should be taught and encouraged. If lifestyle changes and oral agents are unsuccessful, or in the presence of significant hyperglycemia with or without acute metabolic decompensation, the patient may need to be started on insulin therapy directly. The initial oral agent can be (in alphabetical order) an alpha-glucosidase inhibitor, a biguanide, a glitinide, a sulfonylurea, or a thiazolidinedione; the choice depends on the following points: Table 5. Target Lipid Values by Level of Risk Target values

Level of risk (definition)

Very high (10-year risk of CAD ⬎30%, or history of CAD or diabetes) High* (10-year risk 20 –30%) Moderate† (10-year risk 10 – 20%) Low‡ (10-year risk ⬍10%)

LDL cholesterol (mmol/L)

Total:HDL cholesterol ratio

TG (mmol/L)

⬍2.5

⬍4

⬍2.0

⬍3.0 ⬍4.0

⬍5 ⬍6

⬍2.0 ⬍2.0

⬍5.0

⬍7

⬍3.0

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For those with persistent hyperglycemia (FPG ⱖ7 mmol/L or HgA1c ⬎7%), metformin, a glitinide, or a sulfonylurea may be chosen as a first agent. Metformin is associated with less weight gain and less hypoglycemia than sulfonylureas or glitinides, and for these reasons it is often the drug of first choice. Metformin is contraindicated in the presence of significant renal or hepatic insufficiency, as it may cause lactic acidosis. Acarbose may be added to diet or metformin or sulfonylurea therapy to improve glucose control, but gastrointestinal side effects may be a limiting factor. Thiazolidinediones may be used alone or in combination with the other oral agents listed above. Liver function tests should be performed at regular intervals while on this drug. If target glucose levels are not attainable with a single agent, an agent or agents from another class may be added until the maximum dose of an agent of each class is reached. If individual treatment goals have not been reached on a regimen of diet, exercise, and oral agents, then insulin therapy should be initiated to improve glycemic control. When insulin therapy is initiated, the concomitant use of oral agents is an acceptable option. When insulin therapy is added to oral agents, a single injection of intermediate-acting insulin may be added at bedtime.

Poor glucose control despite insulin therapy can be improved by the addition of either acarbose or metformin.

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Data adapted from Fodor. CAD, coronary artery disease; HDL, High-density lipoprotein; LDL, lowdensity lipoprotein; TG, triglycerides. *Start medication and lifestyle changes concomitantly if values are above target values. † Start medication if target values are not achieved after 3 months of lifestyle modification. ‡ Start medication if target values are not achieved after 6 months of lifestyle modification.

Fig 1.

Predictors for PTDM at 1 year posttransplant.

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While caring for transplant patients with diabetes, a consultation with an endocrinologist or a diabetes specialist may be appropriate, depending on the individual needs of the patient or resources of the transplant facility.

REFERENCES 1. Alberti KGMM, Zimmet PZ, et al: WHO 1:2, 1999 2. Mathews CE, Leiter EH: Diabetes 48:2189, 1999 3. Viberti G: Transplant Proc 33(Suppl 5A):3S, 2001 4. Stratton IM, Adler AI, Neil HA, et al: BMJ 321:405, 2000 5. Cosio GF, et al: Kidney Int 62:1440, 2002 6. Dubernard JM, Frei U: Transplant Proc 33(Suppl 5A):1S, 2001 7. Chilcott JB, Witby SM, Moore R: Transplant Proc 33(Suppl 5A):3S, 2001 8. Marchetti P: Transplant Proc 33(Suppl 5A):27S, 2001 9. Weir MR, Fink JC: Am J Kidney Dis 34:1, 1999 10. Krentz AJ, Dmitrewski J, Mayer D, et al: Clin Immunother 4:103, 1995 11. Krentz AJ, Dousset B, Mayer D, et al: Diabetes 42:1753, 1993 12. Knoll GA: BMJ 318:1104, 1999 13. Reisaeter AV, Hartmann A: Transplant Proc 33(Suppl 5A):8S, 2001 14. Scantlebury V, Shapiro R, Fung J, et al: Transplant Proc 23:3169, 1991 15. Robert JJ, Tete MJ, Crosnier H, et al: Ann Pediatr (Paris) 40:112, 1993 16. Jardine A: Transplantation 72(12 Suppl):S81, 2001 17. Fodor JG, Frohlich JJ, Genest JJ, et al: CMAJ 162:1441, 2000 18. Al-Uzri A, Stablein DM, A Cohn R: Transplantation 72: 1020, 2001 19. Meltzer S, Leiter L, Daneman D, et al: CMAJ 159(8 Suppl), 1998 20. Kasiske B, et al: The epidemic of diabetes mellitus in the ESRD population. USRDS ASN Talk 2001

Fig 2. Proposed algorithm for screening and managing diabetes in transplantation.