Panc presentation biochem dept feb2010

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  • Heidelberg
  • Fasting glucose 4.2, 2 hour 13.2
  • Arginine to Histine
  • HbA1c 7.9Insulin:Mixtard 16u mane, 10 nocte, no hypos

Transcript

  • 1. Simultaneous kidney-pancreas transplantationRichard OramAcademic Clinical FellowNephrology
  • 2. Summary Case presentations  History of diabetes  Clinical course (SPK)  Points of interest Kidney pancreas transplantation  Basics  Risks/benefits with kidney pancreas transplantation (SPK)  Try to get UCPCR in somewhere….
  • 3. Case 1 Mrs PP Type 1 Diabetes- diagnosed 1974 Proliferative retinopathy, treated and stable Peripheral Neuropathy-problems soft tissue infection Rt foot Diabetic Nephropathy- CKD STAGE 4 when referred to nephrology Identical twin
  • 4. Initial Management Management of complications of Diabetic nephropathy  Anaemia;-EPO and iv iron  CKD MBD;1-alpha calcidol, phosphate binder  Blood pressure control Transplant discussions/work up  Keen to consider transplant  Identical twin  Discussions re kidney pancreas potential also
  • 5. Why Transplant?Kidney Rationale  Significant mortality advantage to having a renal transplant  Without, survival <10 years (cardiovascular mortality)  But why decide on pancreas now?
  • 6. Projected years of life(at time of placement on waiting list Years 1991–97) 35 Non-diabetic dialysis 30 Non-diabetic Tx Diabetic dialysis 25 Diabetic Tx 20 15 10 5 0 20–39 40–59 60–74 Age (yrs) Wolfe et al. (1999)
  • 7. Transplant work up Living donor transplant considered potential option Twin referred for assessment Question raised “What are my chances of developing diabetes?” Found to be strongly positive GAD and ISLET antibodies Further discussion –withdrawn as potential donor
  • 8. Mrs PP Transplant Workup Cardiac  Immunological Vascular  HLA matching Malignancy  Panel reactive antibodies Infection Thrombophilia  Cross match at time of Bladder surgery Virus (Hep B/C/HIV, CMV) Compliance
  • 9. Kidney pancreas Trx Work up Seen in Oxford Now on Haemodialysis Problems with hypo unawareness Accepted for list
  • 10. Kidney - pancreas transplantationCombined Kidney Pancreas Rationale Improve patient and graft survival  Better glycaemic control  Immunosuppressed anyway Prevent or reverse diabetic complications Improve quality of life  dialysis and insulin independent (60% 5 year)
  • 11. SPK transplantation improves patient survival when compared with cadaveric kidney transplantation Txp type 10 yr patient survival [%] Projected life yrs SPK 67 23.4 KTA LRD 65 20.9 KTA Cad 46 12.9 From Ojo et al, AST May 2000 UNOS/USRDS: 17,137 diabetic txps 1988 - 1997
  • 12. First year survival disadvatage for SPK Morath et al, JASN 2008
  • 13. Functioning Kidney <10years post Tx Morath et al, JASN 2008
  • 14. Functioning pancreas >10 years post Tx Morath et al, JASN 2008
  • 15.  So long term data to suggest benefit…. What about complications?
  • 16. Effect of SPK transplantation on diabetic complications Microvascular disease  Retinopathy  Neuropathy  Nephropathy Macrovascular disease  Cardiovascular  Cerebrovascular  Peripheral vascular disease
  • 17. Effect of SPK transplantation on retinopathy  No change, sometimes worse  no proper trials or studies  Is diabetic eye disease too far advanced by the time patient receives a SPK txp ?
  • 18. Effect of SPK transplantation on diabetic neuropathy10 year study of diabetics with and without functioningpancreatic allograftsMinneapolisAnn Neurology 1997 1] Clinical evaluation and autonomic tests improved slightly 2] Motor and sensory conduction indices significantly better 3] Improvement may take some time [2 years] 4] Significant deterioration in diabetic controls
  • 19. Diabetic NephropathyTime [yrs] GBM thickness Mesangial cell Mean glomerular [nm] volume volume**Baseline 594 + 81 0.10 + 0.03 2.14 + 0.625 570 + 64 0.12 + 0.04 1.73 + 0.3810 404 + 38 0.10 + 0.02 1.50 + 0.36 Fioretto et al, NEJM, 1998
  • 20. Microvasc disease summary Evidence to support improvement post transplant Neuropathy>nephropathy>retinopathy Benefit outlives insulin independance
  • 21. Effect of SPK transplantation on other Macrovasc complications May make macroangiopathy worse Recent European data suggest that it may take at least 5 years to get better Improvement in outcomes due to reduced cardiac events
  • 22. Why not ‘cure diabetes’earlier? High perioperative mortality when other treatments are available Issues with rejection and sensitisation  Make future kidney transplant harder  Hard to detect rejection Issues with long term immunosuppression  Infection  Cancer  Drug toxicity Sometimes indicated  Severe Hypoglycaemia  PTA more common in USA  Islets
  • 23. Balance of rejection v Drug toxicity Creatinine is very sensitive marker of kidney (+pancreas) rejection High immunosuppressant levels esp Tacrolimus can also cause acute and chronic kidney injury Faced with an increased creatinine it is normally either  Tacrolimus level  Acute rejection One needs high dose immunosuppression, the other needs reduction  problem!
  • 24. ADA guidelines (T1DM) Established ESRD in patients who qualify for or already have a kidney transplant (SPK or PAK) Frequent acute and severe metabolic complications (hypoglycaemia, hyperglycaemia, DKA) requiring medical attention (PTA) Consistent failure of insulin-based management to prevent acute complications (PTA) Clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating (PTA)
  • 25. Kidney - pancreas transplantation far more common in the US History > 30 years Kelly et al, 1967, Minneapolis Mainly in US 7 designated centres in UKPancreas transplantation 1966 - 1998
  • 26. Kidney - pancreas transplantation: patientselection* Renal failure Dialysis dependent or GFR < 20ml/min Low C peptide Low cardiac risk Minor peripheral or cerebrovascular disease Compliant Usually less than 50 years age Now less than 60 years age * Sollinger et al, Ann Surgery, 1998
  • 27. Transplant Called to Oxford 22/08/2010 Simultaneous pancreas kidney transplant Return to theatre 23/08/2010 for drop in HB Two nights in intensive care Immunosuppression Campath (alemtuzumab ) and steroid induction Tacrolimus and mycophenolate maintainance
  • 28. Exocrine drainage: management of the pancreatic ductBladder drainage Enteric drainage
  • 29. The actual operation
  • 30. Technical failureFrom Gruessner and Sutherland, ClinicalTransplants, 2002
  • 31. Post transplant course Now 1 yr post SPK Cr 127 Off insulin last glucose 5.7 Feels “fantastic”
  • 32. Mrs SC 54 Known MODY  (maturity onset diabetes of the young) Previously enjoyed working as an HCA in hospital
  • 33. Mrs SC Son referred from Chesterfield Hospital 1997 Young onset diabetes Diagnosed on OGTT age 13 “Long honeymoon”, (HbA1c 4.5-5.5 until age 15) Then HbA1c rose and commenced insulin and gained very good control
  • 34. Mrs SC DM diagnosed age 15, always on small amounts of insulin, esp during pregnancies Age 27 stopped insulin due to weight gain Trial of OHA (gliclazide) unsuccessful Back on insulin 2 years later, low doses Retinopathy in early 30s - laser treatment
  • 35. Family history Late 60s OHADMInsulin DM 30s DM teensMI 40s OHAs Insulin DM age 15 insulin retinopathy nephropathy SPK Heterozygous R272H mutation in HNF1a gene Arginine to Histine DM 13 Insulin
  • 36. Mrs SC Post diagnosis of HNF1a MODY Remained on low doses of insulin  No further trial of gliclazide Moved to Cardiff
  • 37. Mrs SC - Cardiff 2000 MI  Thrombolysed  CABG 2001 2005  Nephrology referral  Creatinine 160 (50-110)  ?EPO/?ACEI
  • 38. Mrs SC – nephrology referral Cr 160 (eGFR 31, CKD3/4), proteinuria   NEPHROPATHY Hb 9.9  ANAEMIC Bp 160/90  HYPERTENSIVE
  • 39. Mrs SC nephrology referral ACEI started (bp and proteinuria) EPO and IV iron started (anaemia) Regular follow up
  • 40. Mrs SC Over next 2 years…  Cr drifted up  eGFR 22 by 2007  (CKD 3 30-60, CKD 4 15-30, ESRD <15) Discussion about Renal Replacement Therapy  Dialysis – pt anxious ++  Transplant  Activated on transplant list end of 2007
  • 41. Mrs SC Transplant options  Kidney vs Kidney and Pancreas  Put on Simultaneous Pancreas Kidney (SPK) list  Pre emptive (before dialysis starts)  Specific advantages of early operation in diabetic subjects  Wait longer = more complications=higher surgical risk
  • 42. Mrs SC Transplant workup No OGTT No endocrine review Various parts of patients notes record T1DM, T2DM, IDDM, IDDM with low insulin dose. Does this make sense?
  • 43. Mrs SC Simultaneous Pancreas and Kidney transplant March 2008 Short waiting time  Younger donors/shorter list (benefit) 1 month peri operative stay
  • 44. Mrs SC Peri-operative stay Infection/abcess next to graft  Multiple Abx  Percutaneous drain  Necrosis then debridement of abdo wound Acute rejection (in pancreas and kidney)  Anti Thymocyte Globulin (ATG)
  • 45. Acute rejection Cellular (T cell) 90%  Cellular infiltrate in renal tubules, +/- vascular involvment Humoral (B cell/antibody mediated) 10%  C4d staining on biopsy, blood vessel involvement
  • 46. Mrs SC Cellular rejection  Methylprednisolone 1g for 3 days  Course of treatment dose ATG  Increase baseline immunosuppression
  • 47. Mrs SC discharge Tacrolimus and Mycofenolate immunosuppression No steroids Antibiotics Drain in situ
  • 48. Mrs SC 2 months laterJun 2008 Exploration of wound again MI requiring angiogram Increased creatinine ( renal biopsy no rejection) Neutropenic  Side effect of Mycofenolate stopped and tacrolimus monotherapy
  • 49. Mrs SC Relative stability until Jun 2009  Further increase in Cr to 230  Biopsy acute rejection and chronic scarring  Immunosuppression changed to Tac/rapamycin and steroids  Poor outlook for graft survival, counselled about early graft loss
  • 50. Mrs SCCurrently: Has never worked since transplant, now feels too unwell and has retired Intermittent depression Normal OGTT, tested 3x post transplant
  • 51. Mrs SC Has been told her kidney and pancreas will fail within 2 years Will prob not get another transplant as has been sensitised (anti HLA antibodies) 3 years post transplant prob back on insulin and will need to start dialysis
  • 52. How does SC feel at the moment? “Before surgery I was on insulin, but went to work and enjoyed my job, I did not have to take many pills” “Now I take lots of pills, I cannot work and I wish I never had the operation” “I wish I had been told more before the operation”
  • 53. SC – First HNF1a patient with SPK  Diagnosis not known prior to operation?  Unclear how much of a trial of gliclazide she had  But diabetic complications anyway  Pre procedure data to suggest if she was T1DM that best outcome is with SPK  Higher risk of Iatrogenic illness (early)  Normoglycaemia at moment  But soon back on dialysis and back on insulin
  • 54. With hindsight?........ Borderline age Borderline cardiac status (but does this matter..) Other options? (LDK/DDK/Kidney+Islet/Islet alone) How do we discuss transplant before surgery?  Bristol/Oxford
  • 55. SPK transplantation improves patient survival when compared with cadaveric kidney transplantation Txp type 10 yr patient survival [%] Projected life yrs SPK 67 23.4 KTA LRD 65 20.9 KTA Cad 46 12.9
  • 56. Kidney - pancreas transplantation David Taube (WLRaTC) £56,000 per txp “In the wrong hands:-Mad, bad and frankly dangerous”  When it goes well ……  When it goes badly ……………… “Careful patient selection, good donors and a first class team are pre requisites for success”
  • 57. Questions?
  • 58. SPK transplantation: summary and conclusions Optimal treatment for the young, selected diabetic nephropath Can make people worse Outcome data show benefit over and above kidney transplantion alone Reversal of diabetic complications partial and may take time
  • 59. The end…..