New-Onset Diabetes after Transplantation

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1 New-Onset Diabetes after Transplantation Dr Mahmoud Darouich Ministry of Health - Damascus The tenth conference of syrian society of nephrology and transplantation Mashta-Alhelou 6-8/11/2008

2 Cause of Death in Renal Transplant Recipients With Functioning Transplants ( ) Total CVD: 45.7% 21% 7.40% 13% Cerebrovascular diseas Myocardial infarction Other cardiovascular 13% 20.40% 25.30% Infection Malignancy Other Excludes patients whose cause of death was unknown. US Renal Data System: 1999 Annual Data Report.

3 Cardiovascular Risk Factors in Renal Transplant Recipients vs General Population Risk similar to general population Elevated Total - C Low HDL C Hypertension Risk greater than in general population Age Smoking Diabetes mellitus Single-center retrospective study (N = 1,124) Kasiske BL et al. J Am Soc Nephrol. 2000; 11:

4 Classification of diabetes mellitus Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes mellitus Other specific types ( New-Onset Diabetes after Transplantation )

5 Classification of diabetes mellitus Type 1 diabetes mellitus Type 2 diabetes mellitus Gestational diabetes mellitus Other specific types ( New-Onset Diabetes after Transplantation )

6 PRE-TRANSPLANT DIABETES MELLITUS POST-TRANSPLANT DIABETES MELLITUS (PTDM) NEW ONSET DIABETES MELLITUS (NODM) OR DENOVO PTDM

7 Incidence and prevalence The prevalence of new-onset diabetes after transplantation has been greatly underestimated in the literature because of the lack of a standard definition for the condition.

8 Incidence and prevalence Common definitions of PTDM were as follows: Requirement of insulin >30 consecutive days in patients with no previous history of diabetes Need for either insulin and/or oral hypoglycemic agents

9 Incidence and prevalence Such a definition, while also used in previous literature, fails to capture a great number of individuals on oral medication or who are diet-controlled. Clinical trials do not routinely include oral glucose tolerance test to determine the exact incidence of glycemic abnormalities in transplant recipients.

10 Incidence and prevalence Estimates of the incidence of diabetes vary from 1.8% to 53.6%. The type of immunosuppressive regimen used and patient demographics was found to explain 74% of the variability in incidence.

11 Incidence and prevalence

12 Definition and diagnosis of diabetes after transplantation Diabetes mellitus after transplantation may be diagnosed by any of the following: 1. Symptoms of diabetes ( include polyuria, polydipsia, and unexplained weight loss ) plus casual glucose concentrations > 200 mg/dl. OR 2. Fasting plasma glucose > 126 mg/dl. OR 3. 2 hour plasma glucose > 200 mg/dl during an oral glucose tolerance testing.

13 Natural History The onset of PTDM is usually insidious. In addition, hyperglycemia and new-onset diabetes in these patients may resolve spontaneously over several weeks or months, in some cases without the need for treatment. However, it is important to emphasize that remission of diabetes may not be completed.

14 Natural History The incidence of diabetes after transplantation appears to be biphasic: 1. Most of the cases develop within the first 6 months posttransplant. 2. The cumulative incidence rate slows after the initial 6 months but continues to rise for the remainder of the post-transplant period. Timing may be dependent on immunosuppression regimen. Presentation ketoacidosis is rare.

15 Impact on Graft Function Graft function and survival Proposed mechanisms: Diabetic nephropathy Hypertension Low immunosuppressant doses

16 Impact on Life Expectancy Patient survival Proposed mechanisms: Increased incidence of infections Increased risk of sepsis CVD

17 (NODM) and Patient survival

18 (NODM) and Graft survival

19 Cardiovascular disease after renal transplantation Risk for CVD Proposed mechanisms: Hyperinsulinemia Glucose intolerance Insulin resistance Dyslipidemia Hypertension

20 Cost Associated with NODM Cost associated with treatment and management. Cost associated with co-morbidities related to diabetes. By 2 years post-transplant additional cost of $21,500 per newly diabetic patient (Woodward et al. AJT 2003;3:590 )

21 Risk Factors for NODM HLA phenotype Age>40 years Hepatitis C CMV Cadaver kidney Increased risk for developing diabetes after transplantation Obesity Black race or Hispanic ethnicity Male donor Family history of diabetes Immunosuppressive therapy

22 Management Approach to NODM Potential risk factors after transplantation identified for diabetes Risk Factor Non-modifiable Age 0-17 y y y 60+ y African-American race Hispanic race Hepatitis C infection Family history of DM Modifiable Obesity Corticosteroids Tacrolimus Cyclosporine Azathioprine Mycophenolate mofetil CMV Relative Risk (reference) NA NA 1.53 NA

23 Management Approach to NODM Individualizing immunosuppressive therapy DM Lipids HTN AR Corticosteroids Cyclosporine Tacrolimus Rapamycin MMF? Azathioprine Induction T. Adapted from Jardine et al. (2001)

24 Management Approach to NODM Pre-transplant individualization of immunosuppressive therapy Immunosuppressive therapy should be individualized using the following guidelines: 1. Plan to reduce corticosteroid dose as early as possible in individuals with CV and diabetes risk factors. 2. Steroid-sparing regimens should be considered to allow lower corticosteroid doses to be used. 3. The risk of developing new-onset diabetes after transplantation should be weighed against the risk of acute rejection when choosing an immunosuppressive regimen for any individual patient.

25 Management Approach to NODM Monitoring of the transplant patient All patients should screened for FPG levels at the following intervals: 1. at least once a week for the first 4 weeks post-transplant. 2. at 3, 6, and 12 months post-transplant. 3. Annually after the first year. Plasma glucose levels should also be randomly monitored at regular intervals, preferably when patients present for blood monitoring of plasma immunosuppressant levels. OGTTs should be considered in patients with normal FPG levels.

26 Management Approach to NODM Management of immunosuppressive therapy 1. Reduce the dose of steroids as soon as possible. 2. Consideration of the risk of developing new-onset diabetes after transplantation should be weighed against the risk of acute rejection when choosing an immunosuppressive regimen for any individual patient. 3. Switching from tacrolimus to cyclosporine may be beneficial if diabetes has developed and is difficult to control.

27 Management Approach to NODM Monitoring for the transplant patient with new-onset diabetes Self-monitoring: should be an essential component of the therapeutic plan of all patients taking insulin therapy and an integral component of the therapeutic plan of patients taking oral agents. Self-monitoring may also be useful for patients whose diabetes is controlled by diet therapy alone. Lipid levels: A1c levels: should be measured every 3 months. An A1c level of 6.5% or higher is recommended for therapeutic intervention. Diabetic complications: all patients should be screened annually to detect the development of the long-term complications associated with diabetes, including retinopathy and neuropathy.

28 Stepwise approach to treatment of NODM Nonpharmacologic Therapy (Weight Loss; Exercise( Oral Hypoglycemic Agent Monotherapy? Manipulation of Immunosuppression Combination of Oral Agents Insulin Plus Oral Agents Insulin Monotherapy

29 Reversibility of NODM Wean patients off of exogenous insulin as doses of immunosuppressants were reduced to maintenance levels. PTDM can be self-corrected as doses of immunosuppressants decline post transplant. Patients should be monitored to prevent hypoglycemia.

30 New-Onset Diabetes after Transplantation Retrospective study on 192 transplanted pts in Syria between feb/2001 Till oct 2003

31 New-Onset Diabetes after Transplantation Diabetic pt. Non diabetic pt.

32 New-Onset Diabetes after Transplantation % PTDM 151 Non PTDM

33 New-Onset Diabetes after Transplantation The median time of onset was 56.6 days. ( 4 days 21 months )

34 New-Onset Diabetes after Transplantation Risk factor ( age ) Incidence of new-onset diabetes after transplantation 40.00% 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 19.25% 14.40% 35.50% Age < 45 y Age > 45 y

35 New-Onset Diabetes after Transplantation Risk factor ( BW ) Incidence of new-onset diabetes after transplantation 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 19.25% 13.50% 33.30% BW < 70 kg BW > 70 kg

36 New-Onset Diabetes after Transplantation Risk factor ( Male donor ) Incidence of new-onset diabetes after transplantation 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 19.25% 16.00% 22.00% Female donor Male donor

37 New-Onset Diabetes after Transplantation Risk factor ( Hepatitis C infection ) Incidence of new-onset diabetes after transplantation 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 19.25% 20.70% 6.60% HCV - HCV +

38 New-Onset Diabetes after Transplantation Risk factor ( Family history ) Incidence of new-onset diabetes after transplantation 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 19.25% 15.80% 25.00% No family history With family history

39 New-Onset Diabetes after Transplantation Risk factor ( HLA-A2 phenotype ) Incidence of new-onset diabetes after transplantation 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 19.25% 30.40% 13.80% No HLA-A2 phenotype HLA-A2 phenotype

40 New-Onset Diabetes after Transplantation Risk factor ( immunosuppressive therapy ) Incidence of new-onset diabetes after transplantation 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% 22.00% 19.25% 14.00% 7.40% TAC Cys RAP

41 New-Onset Diabetes after Transplantation Management Pt. No 8 Pt. ( 22.2% ) 9 Pt. ( 25% ) 19 Pt. ( 52.7% ) PTDM Therapy Nonpharmacology therapy 19.25% Oral agent therapy Insulin therapy Remission 1 Pt. ( 12.5% ) 3 Pt. ( 33.3% ) 4 Pt. ( 21% )

42 New-Onset Diabetes after Transplantation Another Retrospective study on 49 transplanted pts in Syria between 2/2004 Till 11/2007

43 New-Onset Diabetes after Transplantation Tac cys

44 New-Onset Diabetes after Transplantation Incidence of new-onset diabetes after transplantation 12.00% 10.00% 8.00% 6.00% 4.00% 2.00% 0.00% 7.60% 11.20% TAC Cys

45 Summary 1. PTDM is common, affecting ~ 25% of kidney transplant recipients at 3 years 2. Pathogenic mechanisms are multifactorial 3. PTDM may increase risk of graft loss and mortality and certainly adds to the economic burden of transplantation 4. Modifiable risk factors include obesity and immunosuppression 5. Studies needed to assess combinations of immunosuppression and risk for PTDM 6. Management is multifaceted

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