Richard Smith Consultant Senior Lecturer Renal Medicine Southmead Hospital Bristol

1. New Onset Diabetes after Transplantation: a non-modifiable risk factor for cardiovascular disease Richard Smith Consultant Senior Lecturer Renal Medicine Southmead Hospital Bristol

2. Published literature on NODAT ?

3. Causes of graft loss after one year Commonest cause of patient death is cardiovascular disease

4. “Diabetes is a condition of premature cardiovascular mortality associated with abnormal glucose tolerance” J Tooke

5. Management of cardiovascular risk important in transplant population Does development of NODAT represent an additional risk factor for cardiovascular disease If yes can we modify this risk factor

6. Decreased survival post-transplant 67% vs 83% 2 year survival (Friedman et al, Am J Nephrology 1985, 5: 196) Decreased graft survival 48% vs 70% survival (Miles et al, Transplantation 1998, 65:380)

7. Jindal and Hjelmeseth Transplantation 2000 70: SS58

8. How common is NODAT ? Ciclosporin based immunosuppression 3-19% Tacrolimus based immunosuppression 16-20% Significant differences between studies in: Definition of NODAT Doses of calcineurin inhibitors used Corticosteroid usage

9. NODAT matters

10. Risk factors for NODAT Age Race Gender Family history of diabetes Obesity Cytomegalovirus infection HLA B27, A26, A30, B8, B18 Autosomal dominant polycystic kidney disease Prednisolone dose Type of Calcineurin inhibitor (ciclosporin versus tacrolimus) Calcineurin inhibitor dose

11. RR = 2.87 (1.24-6.65) p = 0.016 De Mattos et al Kidney International 7(2):714-20 (2005)

12. Common beliefs NODAT caused by calcineurin inhibitors NODAT more common with tacrolimus than ciclosporin based immunosuppression NODAT caused by corticosteroids Obesity is a dominant risk factor

13. K+ VDCC KATP ACh CCK Guanine nucleotides Ca2+ ATP Glucose Glucose-6-P Insulin secretion GLUT PKs GK Glucose How does the -cell respond to glucose? Role of immunosuppressive drugs MPA Rapamycin Corticosteroids Calcineurin CnI mRNA NFAT

14. This cannot explain pathophysiology of NODAT as the majority of patients who receive these drugs do not develop diabetes

15. 120 % cell survival 100 80 60 0 0 0.1 1 10 100 Tacrolimus (ng/ml) Effect of 72h in vitro exposure to tacrolimus on human islet survival

16. 120 % cell survival 100 90 80 0 1 10 0 0.1 Rapamycin (ng/ml) Effect of 72h in vitro exposure to rapamycin on human islet survival

17. Retrospective study of outcomes January 1995 - October 2001 Retrospective study of outcomes September 2004 - October 2007 Prospective study of live donor kidney transplant recipients May 2008 – April 2009

18. New Onset Diabetes following Transplantation (NODAT) WHO and ADA Criteria (Diabetes Care 2000: 23 Suppl1: S4) All types of diabetes: • Plasma glucose greater than 7 mmol/l in the fasting state • Plasma glucose  11.1 mmol/l 120 minutes following a 75g glucose load • A random glucose measurement with symptoms 11.1mmol/l or two repeated random glucose measurements without symptoms  11.1mmol/l

19. Retrospective study January 1995 – October 2001 Diabetic patients n = 32 Non-diabetic patients n = 353 Ciclosporin n = 167 Tacrolimus n = 94 Conversions n = 92 68 patients developed NODAT within 3 months of Tx No patients developed NODAT >3 and ≤12 months post Tx 38 patients diabetic at 1 year (11%) Ciclosporin n = 15 (9%) Tacrolimus n = 10 (11%) Conversions n = 13 (14%)

20. Retrospective study September 2004 to October 2007 Diabetic patients n = 38 Non-diabetic patients n = 268 42 patients developed NODAT within 3 months of Tx Mean 48.2 days Median 34.5 days No patients developed NODAT >3 and ≤12 months post Tx 20 patients stopped hypoglycaemic medication 0-1 months 6 2-3 months 6 4-12 months 8 22 patients diabetic at 1 year (8%)

21. 20/42 patients were demonstrated to have normal random blood glucose measurements off-hypoglycaemic treatment at 1 year This cohort were offered an Oral Glucose Tolerance Test (OGTT) 3 of the 22 patients with ‘resolved’ NODAT had died 6 did not reply 11 OGTTs were performed 3 were normal 3 revealed impaired glucose tolerance (IGT) 5 showed on going diabetes

23. Autosomal-Dominant Polycystic Kidney Disease P = 0.041

24. Tacrolimus

25. Ciclosporin

26. Prednisolone

27. On multivariate analysis age was the only significant risk factor for development of NODAT

30. Patients receiving LKD Tx between May 2008 and April 2009 • 28 patients approached of whom 18 consented to take part • All had normal screening according to BTS guidelines • OGTT • Arginine IVGTT • Euglycaemic hyperinsulinaemic clamp

31. Pre-transplant OGTT 12 normal 4 IGT 2 diabetes Mean ages were 39.3, 54.6 and 62.3 years respectively 7 patients studied pre and 3 month post-transplant No acute rejection 7.5mg prednisolone OGTT 5.5-7.8 FPG 4.4-5.6 HbA1c 5.2-5.2

32. Acute insulin response Glucose Arginine

33. Glucose tolerance Age

34. Glucose tolerance Age

35. Glucose tolerance Transplantation Age

36. Glucose tolerance Transplantation Age

37. Conclusions Transplantation causes a deterioration in glucose homeostasis in all patients Those with abnormal glucose homeostasis pre-transplant are at most risk of developing NODAT The determinants of this pre-transplant status are not modifiable Patients who develop NODAT will have already accrued excess CV disease pre-transplant CV risk is increased by transplantation as a result of deterioration in glucose homeostasis whether or not NODAT results

38. Diabetes Prevention Study 2 n= 3234 IGT aged 25-85 yrs NEJM 2002:346; 393

39. Alternatives • Corticosteroid free primary immunosuppression • CsA or tacrolimus monotherapy • Monoclonal antibody + CnI +/- MMF • Low dose CnI • Monoclonal antibody + tacrolimus + rapamycin • Monoclonal antibody + tacrolimus + MMF • CsA + rapamycin + corticosteroid • Conversion to CnI free regimen on diagnosis of PTDM • Conversion to MMF • Conversion to rapamycin • Both require continuation of prednisolone

40. Effects of Immunosuppressive Drugs Ciclosporin, tacrolimus and corticosteroids all shown to be diabetogenic Paucity of data on mycophenolate mofetil and rapamycin Corticosteroids Cause insulin resistance May also inhibit insulin secretion - through a reversible reduction in insulin mRNA synthesis

41. Tacrolimus Reversible time + dose dependent reduction in insulin secretion - due to inhibition of insulin mRNA transcription Interrupts Ca2+-calmodulin-calcineurin signalling pathway which plays a fundamental role in maintenance of insulin gene expression via NFAT binding to insulin promoter High content of FKBP-12 in b cells may facilitate the accumulation of tacrolimus in b cells Morphological effects : degranulation, vacuolization, swelling of RER, Golgi + Mitochondria

42. Ciclosporin Inhibits calcineurin signalling pathway affecting insulin release as for tacrolimus Reduces insulin secretion by inhibition of voltage-dependent calcium transport Impairs intracellular transport of insulin from sites of synthesis to secretory granules Morphological effects : degranulation, vacuolization, swelling of RER, Golgi + Mitochondria Rapamycin Suggested inhibition of insulin gene transcription

43. Mycophenolate Mofetil • MPA inhibits insulin secretion induced by glucose Glucose metabolism generates guanine nucleotides that synergize with Ca2+ in the stimulation of insulin secretion • MPA specifically depletes cellular GNs Cell viability is unaffected