1. Simultaneous kidney-
pancreas transplantation
Richard Oram
Academic Clinical Fellow
Nephrology

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 Further discussion –withdrawn as potential donor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 transplantation
Combined 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
neuropathy
10 year study of diabetics with and without functioning
pancreatic allografts
Minneapolis
Ann 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 Nephropathy
Time [yrs] GBM thickness Mesangial cell Mean glomerular
[nm] volume volume**
Baseline 594 + 81 0.10 + 0.03 2.14 + 0.62
5 570 + 64 0.12 + 0.04 1.73 + 0.38
10 404 + 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
UK
Pancreas transplantation 1966 - 1998

26. Kidney - pancreas transplantation: patient
selection*
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 duct
Bladder drainage Enteric drainage

29. The actual operation

30. Technical failure
From Gruessner and Sutherland, Clinical
Transplants, 2002

31. Post transplant course
 Now 1 yr post SPK
 Cr 127
 Off insulin last glucose 5.7
 Feels “fantastic”

33. Mrs SC
 54
 Known MODY
 (maturity onset diabetes of the young)
 Previously enjoyed working as an HCA in hospital

34. 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

35. 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

36. Family history
Late 60s
OHA
DM
Insulin DM 30s DM teens
MI 40s OHAs Insulin
DM age 15
insulin
retinopathy
nephropathy
SPK
Heterozygous
R272H mutation in
HNF1a gene
Arginine to Histine
DM 13
Insulin

37. Mrs SC
 Post diagnosis of HNF1a MODY
 Remained on low doses of insulin
 No further trial of gliclazide
 Moved to Cardiff

38. Mrs SC - Cardiff
 2000 MI
 Thrombolysed
 CABG 2001
 2005
 Nephrology referral
 Creatinine 160 (50-110)
 ?EPO/?ACEI

39. Mrs SC – nephrology referral
 Cr 160 (eGFR 31, CKD3/4), proteinuria
  NEPHROPATHY
 Hb 9.9  ANAEMIC
 Bp 160/90  HYPERTENSIVE

40. Mrs SC nephrology referral
 ACEI started (bp and proteinuria)
 EPO and IV iron started (anaemia)
 Regular follow up

41. 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

42. 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

43. 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?

44. Mrs SC
 Simultaneous Pancreas and Kidney transplant
March 2008
 Short waiting time
 Younger donors/shorter list (benefit)
 1 month peri operative stay

45. 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)

46. 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

47. Mrs SC
 Cellular rejection
 Methylprednisolone 1g for
3 days
 Course of treatment dose
ATG
 Increase baseline
immunosuppression

48. Mrs SC discharge
 Tacrolimus and Mycofenolate
immunosuppression
 No steroids
 Antibiotics
 Drain in situ

49. Mrs SC 2 months later
Jun 2008
 Exploration of wound again
 MI requiring angiogram
 Increased creatinine ( renal biopsy no rejection)
 Neutropenic
 Side effect of Mycofenolate stopped
and tacrolimus monotherapy

50. 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

51. Mrs SC
Currently:
 Has never worked since transplant, now feels too
unwell and has retired
 Intermittent depression
 Normal OGTT, tested 3x post transplant

52. 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

53. 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”

54. 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

55. 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

56. 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

57. 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”

58. Questions?

59. 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

60. The end…..