Simultaneous

kidney-pancreas

transplantationRichard OramAcademic Clinical Fellow Nephrology

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 1991–97)

0

5

10

15

20

25

30

35

20–39 40–59 60–74

Age (yrs)

Years

Non-diabetic dialysis

Non-diabetic Tx

Diabetic dialysis

Diabetic Tx

Wolfe et al. (1999)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Further discussion –withdrawn as potential donor

Mrs PP Transplant Workup

Cardiac

Vascular

Malignancy

Infection

Thrombophilia

Bladder

Virus (Hep B/C/HIV, CMV)

Compliance

Immunological

HLA matching

Panel reactive antibodies

Cross match at time of surgery

Kidney pancreas Trx Work up

Seen in Oxford

Now on Haemodialysis

Problems with hypo unawareness

Accepted for list

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)

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

UNOS/USRDS: 17,137 diabetic txps 1988 - 1997

From Ojo et al, AST May 2000

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 Neuropathy Nephropathy

Macrovascular disease Cardiovascular Cerebrovascular Peripheral vascular disease

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 neuropathy

10 year study of diabetics with and without functioning pancreatic allograftsMinneapolisAnn Neurology 1997 1] Clinical evaluation and autonomic tests

improved slightly2] Motor and sensory conduction indices significantly better3] Improvement may take some time [2 years]4] Significant deterioration in diabetic controls

Diabetic Nephropathy

Time [yrs] GBM thickness [nm]

Mesangial cell volume

Mean glomerular 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

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 yearsKelly et al, 1967, MinneapolisMainly in US7 designated centres in UK

Pancreas transplantation 1966 - 1998

Kidney - pancreas transplantation: patient selection*

Renal failureDialysis dependent or GFR < 20ml/minLow C peptideLow cardiac riskMinor peripheral or cerebrovascular diseaseCompliantUsually less than 50 years ageNow 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

duct

Bladder drainage Enteric drainage

The actual operation

Technical failure

From Gruessner and Sutherland, Clinical Transplants, 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

DM age 15insulinretinopathy nephropathySPK

DM 13Insulin

DMInsulinMI 40s

Late 60sOHA

DM 30sOHAs

DM teensInsulin

HeterozygousR272H mutation in HNF1a geneArginine to Histine

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 HYPERTENSIVE

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)

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

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 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

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 SC

Currently:

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 feelat 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”

Questions?

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

The end…..