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Simultaneous kidney-pancreas transplantationRichard OramAcademic Clinical FellowNephrology
Summary Case presentations  History of diabetes  Clinical course (SPK)  Points of interest Kidney pancreas transplant...
Case 1 Mrs PP Type 1 Diabetes- diagnosed 1974 Proliferative retinopathy, treated and stable Peripheral Neuropathy-prob...
Initial Management Management of complications of Diabetic  nephropathy   Anaemia;-EPO and iv iron   CKD MBD;1-alpha ca...
Why Transplant?Kidney Rationale   Significant mortality advantage to having a renal    transplant   Without, survival <1...
Projected years of life(at time of placement on waiting list  Years        1991–97)   35                             Non-d...
Transplant work up Living donor transplant considered potential  option Twin referred for assessment Question raised “W...
Mrs PP Transplant Workup Cardiac                     Immunological Vascular                    HLA matching Malignanc...
Kidney pancreas Trx Work up Seen in Oxford Now on Haemodialysis Problems with hypo unawareness Accepted for list
Kidney - pancreas transplantationCombined Kidney Pancreas Rationale Improve patient and graft survival   Better glycaemi...
SPK transplantation improves patient survival  when compared with cadaveric kidney               transplantation   Txp typ...
First year survival disadvatage for SPK                               Morath et al, JASN 2008
Functioning Kidney <10years post Tx                               Morath et al, JASN 2008
Functioning pancreas >10 years post Tx                                 Morath et al, JASN 2008
 So long term data to suggest benefit…. What about complications?
Effect of SPK transplantation on diabetic                   complications Microvascular disease   Retinopathy   Neuropa...
Effect of SPK transplantation on retinopathy                           No                            change, sometimes   ...
Effect of SPK transplantation on diabetic                       neuropathy10 year study of diabetics with and without func...
Diabetic NephropathyTime [yrs]     GBM thickness   Mesangial cell      Mean glomerular               [nm]            volum...
Microvasc disease summary Evidence to support improvement post  transplant Neuropathy>nephropathy>retinopathy Benefit o...
Effect of SPK transplantation on other           Macrovasc complications May make  macroangiopathy worse Recent European...
Why not ‘cure diabetes’earlier? High perioperative mortality when other treatments  are available Issues with rejection ...
Balance of rejection v Drug toxicity Creatinine is very sensitive marker of kidney  (+pancreas) rejection High immunosup...
ADA guidelines (T1DM) Established ESRD in patients who qualify for or already  have a kidney transplant (SPK or PAK) Fre...
Kidney - pancreas transplantation far more common in the US                                             History           ...
Kidney - pancreas transplantation: patientselection*                                    Renal failure                     ...
Transplant Called to Oxford 22/08/2010 Simultaneous pancreas kidney transplant Return to theatre 23/08/2010 for drop in...
Exocrine drainage: management of               the pancreatic ductBladder drainage              Enteric drainage
The actual operation
Technical failureFrom Gruessner and Sutherland, ClinicalTransplants, 2002
Post transplant course Now 1 yr post SPK Cr 127 Off insulin last glucose 5.7 Feels “fantastic”
Mrs SC 54 Known MODY   (maturity onset diabetes of the young) Previously enjoyed working as an HCA in hospital
Mrs SC Son referred from Chesterfield Hospital 1997 Young onset diabetes Diagnosed on OGTT age 13 “Long honeymoon”, (H...
Mrs SC DM diagnosed age 15, always on small amounts  of insulin, esp during pregnancies Age 27 stopped insulin due to we...
Family history                                    Late 60s                                    OHADMInsulin   DM 30s       ...
Mrs SC Post diagnosis of HNF1a MODY Remained on low doses of insulin   No further trial of gliclazide Moved to Cardiff
Mrs SC - Cardiff 2000 MI   Thrombolysed   CABG 2001 2005   Nephrology referral   Creatinine 160 (50-110)   ?EPO/?ACEI
Mrs SC – nephrology referral Cr 160 (eGFR 31, CKD3/4), proteinuria    NEPHROPATHY Hb 9.9  ANAEMIC Bp 160/90  HYPERT...
Mrs SC nephrology referral ACEI started (bp and proteinuria) EPO and IV iron started (anaemia) Regular follow up
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...
Mrs SC Transplant options   Kidney vs Kidney and Pancreas   Put on Simultaneous Pancreas Kidney (SPK) list   Pre empti...
Mrs SC Transplant workup No OGTT No endocrine review Various parts of patients notes record  T1DM, T2DM, IDDM, IDDM wit...
Mrs SC Simultaneous Pancreas and Kidney transplant  March 2008 Short waiting time   Younger donors/shorter list (benefi...
Mrs SC Peri-operative stay Infection/abcess next to graft   Multiple Abx   Percutaneous drain   Necrosis then debridem...
Acute rejection Cellular (T cell) 90%   Cellular infiltrate in renal tubules, +/- vascular     involvment Humoral (B ce...
Mrs SC Cellular rejection   Methylprednisolone 1g for     3 days   Course of treatment dose     ATG   Increase baselin...
Mrs SC discharge Tacrolimus and Mycofenolate  immunosuppression No steroids Antibiotics Drain in situ
Mrs SC 2 months laterJun 2008 Exploration of wound again MI requiring angiogram Increased creatinine ( renal biopsy no...
Mrs SC Relative stability until Jun 2009   Further increase in Cr to 230   Biopsy acute rejection and chronic scarring ...
Mrs SCCurrently: Has never worked since transplant, now feels too  unwell and has retired Intermittent depression Norma...
Mrs SC Has been told her kidney and pancreas will fail  within 2 years Will prob not get another transplant as has been ...
How does SC feel         at the moment? “Before surgery I was on insulin, but went  to work and enjoyed my job, I did not...
SC – First HNF1a patient with SPK  Diagnosis not known prior to operation?  Unclear how much of a trial of gliclazide sh...
With hindsight?........ Borderline age Borderline cardiac status (but does this matter..) Other options? (LDK/DDK/Kidne...
SPK transplantation improves patient survival  when compared with cadaveric kidney               transplantation   Txp typ...
Kidney - pancreas transplantation David Taube (WLRaTC) £56,000 per txp “In the wrong hands:-Mad, bad and frankly  dange...
Questions?
SPK transplantation: summary and           conclusions Optimal treatment for the young, selected  diabetic nephropath Ca...
The end…..
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 of "Panc presentation biochem dept feb2010"

    1. 1. Simultaneous kidney-pancreas transplantationRichard OramAcademic Clinical FellowNephrology
    2. 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. 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. 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. 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. 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. 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. 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. 9. Kidney pancreas Trx Work up Seen in Oxford Now on Haemodialysis Problems with hypo unawareness Accepted for list
    10. 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. 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. 12. First year survival disadvatage for SPK Morath et al, JASN 2008
    13. 13. Functioning Kidney <10years post Tx Morath et al, JASN 2008
    14. 14. Functioning pancreas >10 years post Tx Morath et al, JASN 2008
    15. 15.  So long term data to suggest benefit…. What about complications?
    16. 16. Effect of SPK transplantation on diabetic complications Microvascular disease  Retinopathy  Neuropathy  Nephropathy Macrovascular disease  Cardiovascular  Cerebrovascular  Peripheral vascular disease
    17. 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. 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. 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. 20. Microvasc disease summary Evidence to support improvement post transplant Neuropathy>nephropathy>retinopathy Benefit outlives insulin independance
    21. 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. 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. 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. 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. 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. 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. 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. 28. Exocrine drainage: management of the pancreatic ductBladder drainage Enteric drainage
    29. 29. The actual operation
    30. 30. Technical failureFrom Gruessner and Sutherland, ClinicalTransplants, 2002
    31. 31. Post transplant course Now 1 yr post SPK Cr 127 Off insulin last glucose 5.7 Feels “fantastic”
    32. 32. Mrs SC 54 Known MODY  (maturity onset diabetes of the young) Previously enjoyed working as an HCA in hospital
    33. 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. 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. 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. 36. Mrs SC Post diagnosis of HNF1a MODY Remained on low doses of insulin  No further trial of gliclazide Moved to Cardiff
    37. 37. Mrs SC - Cardiff 2000 MI  Thrombolysed  CABG 2001 2005  Nephrology referral  Creatinine 160 (50-110)  ?EPO/?ACEI
    38. 38. Mrs SC – nephrology referral Cr 160 (eGFR 31, CKD3/4), proteinuria   NEPHROPATHY Hb 9.9  ANAEMIC Bp 160/90  HYPERTENSIVE
    39. 39. Mrs SC nephrology referral ACEI started (bp and proteinuria) EPO and IV iron started (anaemia) Regular follow up
    40. 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. 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. 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. 43. Mrs SC Simultaneous Pancreas and Kidney transplant March 2008 Short waiting time  Younger donors/shorter list (benefit) 1 month peri operative stay
    44. 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. 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. 46. Mrs SC Cellular rejection  Methylprednisolone 1g for 3 days  Course of treatment dose ATG  Increase baseline immunosuppression
    47. 47. Mrs SC discharge Tacrolimus and Mycofenolate immunosuppression No steroids Antibiotics Drain in situ
    48. 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. 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. 50. Mrs SCCurrently: Has never worked since transplant, now feels too unwell and has retired Intermittent depression Normal OGTT, tested 3x post transplant
    51. 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. 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. 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. 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. 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. 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. 57. Questions?
    58. 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. 59. The end…..
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