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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….
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
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
Why Transplant?Kidney Rationale Significant mortality advantage to having a renal transplant Without, survival <10 years (cardiovascular mortality) But why decide on pancreas now?
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)
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 Found to be strongly positive GAD and ISLET antibodies Further discussion –withdrawn as potential donor
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 ?
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
Microvasc disease summary Evidence to support improvement post transplant Neuropathy>nephropathy>retinopathy Benefit outlives insulin independance
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
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
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!
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)
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
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
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
Exocrine drainage: management of the pancreatic ductBladder drainage Enteric drainage
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”, (HbA1c 4.5-5.5 until age 15) Then HbA1c rose and commenced insulin and gained very good control
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
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
Mrs SC Post diagnosis of HNF1a MODY Remained on low doses of insulin No further trial of gliclazide Moved to Cardiff
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 Renal Replacement Therapy Dialysis – pt anxious ++ Transplant Activated on transplant list end of 2007
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
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?
Mrs SC Simultaneous Pancreas and Kidney transplant March 2008 Short waiting time Younger donors/shorter list (benefit) 1 month peri operative stay
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)
Mrs SC Cellular rejection Methylprednisolone 1g for 3 days Course of treatment dose ATG Increase baseline immunosuppression
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 rejection) Neutropenic Side effect of Mycofenolate stopped and tacrolimus monotherapy
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
Mrs SCCurrently: Has never worked since transplant, now feels too unwell and has retired Intermittent depression Normal OGTT, tested 3x post transplant
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
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”
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
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
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
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”
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