Pancreas Transplantation - Avera Health 1 Pancreas Transplantation Ahmad Bashar Abdulkarim, MD, PhD,...

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Pancreas Transplantation

Ahmad Bashar Abdulkarim, MD, PhD, FACS

Transplant Surgery

Avera Health Center

Sioux Falls, SD


Facts:

• Diabetes patients with chronic kidney disease (CKD) experience excessive morbidity and mortality

• Simultaneous pancreas and kidney (SPK)Simultaneous pancreas and kidney (SPK) transplantation has been shown to significantly improve quality of life, and increase life expectancy of uremic diabetes patients

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Facts:

• One-year and 5-year pancreas graft survival rates are now comparable with those of kidney, liver, and heart transplants

• Half life of an SPK is about 14 years


• IndicationsA- Simultaneous kidney and pancreas transplant (SPK): ESRD secondary to diabetic nephropathy.

B- Pancreas Transplant alone (PTA):

* Brittle diabetics Brittle diabetics

* Frequent episodes of DKA

* Hypoglycemic unawareness

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• ContraindicationsA- Malignancy:A- Malignancy:

* Screening* Free of recurrence for 2 years before the transplant; this will eliminate about 2/3 of recurrences

-Malignant melanomas, breast Ca, and Colon Ca with higher tumor stages; nodalColon Ca with higher tumor stages; nodal involvement (5 years)- Carcinoma in situ; skin, small incidental renal cell carcinoma (no waiting time)


• Contraindications

B- Infections

Viruses:

HIV: [HAART] Small series show comparable outcomes.

Grossi, PA et al, Transplantation, 2012; 12(4): 1039-1045

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B- Infections

Viruses:

HBsAg+:

KTx; Similar pt and graft survival but higher risk of dying of hepatic failure

PTx; Few reports with encouraging results when using Lamivudine for the first year post transplantation.

Reddy et al, Clin Am J Soc Neph 2011 6(6): 1481-7

Akalin E, Clin Transplant 2005, 19(3): 364-6


B- Infections

Viruses:

HepC: No significant effect on graft or patient survival, small reports.

Miguel M et al, Transplantation 2010; 90(1):61-67

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Results of SPK Transplantation in The USA


T1DM vs T2DMT1DM vs.T2DM

-Obesity, and later age of onset, for example, often blur the diagnosis between T1DM vs. T2DM.

-C-peptide (renal failure/gastroparesis.. False elevation)

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T2DMT2DMThe pathophysiology of T2DM includes genetic causes of

chronic inflammation and insulin resistance leading to hyperinsulinemia, which ultimately results in beta-cell exhaustion.

T1DMPatients classically suffer autoimmune-mediated damage to beta cells leading to decreased (or absent) insulin secretion.


Given the increasing prevalence of T2DM in most westernGiven the increasing prevalence of T2DM in most western countries, and

Given that T2DM is among the leading causes of kidney disease,

Therefore, pancreas transplantation may

be underutilized in this population. Currently,

• 8% of SPKs in the USA are performed for T2DM, and 5% and 1% for PAK and PTA, respectively

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Indications for SPK in T2DMIndications for SPK in T2DM-BMI <28

-Insulin dependence (<1 unit/kg/day)

-C peptide >2ng/ml


• Types:

A- Simultaneous pancreas and kidney transplant (SPK).

B- Pancreas after kidney (PAK)

C- Pancreas transplant alone (PTA)

D- Islet Transplantation

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D O tiDonor Operation

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Recipient Operation

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• Types of Pancreas Functions

A- Exocrine:

-Amylase

-Lipase

-Bicarbonate…..

B- Endocrine:

-Insulin

-Glucagon

-Somatostatin….

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• Types of Pancreas Functions

A- Exocrine:

-Amylase

-Lipase

-Bicarbonate….

B- Endocrine:

-Insulin Pancreas Islet Transplant

-Glucagon…..


Islet Transplantation

IndicationThis therapy is only suitable in its current form for patients with

unstable glycemic control that cannot be corrected by standard conventional and intensive insulin therapies

Shapiro, N Engl J Med, 2000, 343 (4):230

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Islet Transplantation

Not currently considered for islet transplantation

1- Patients with good glycemic control

2- Children are not currently considered for islet transplantation

Shapiro, N Engl J Med, 2000, 343 (4):230


Islet Transplantation vs. Insulin Pump

Hgb A1c Corrected Varies

Diabetic Nephropathy Progression No effect

Shapiro, Curr opin organ transplant, 2011, 16(6): 627

Thompson, Transplantation 2011, 91(3): 373

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• Types: (Based on drainage of donor duodenum)

A- Bladder-drained

B- Enteric-drained

(Based on venous drainage)(Based on venous drainage)

A- Systemic

B- Portal

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Bladder-drained Pancreas

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Systemic-enteric Pancreas

Systemic-enteric SPK

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Portal vs. Systemic Drainage Pancreas Tx

Systemic vs. Portal Drainage

• Bypassing the liver causes peripheral hyperinsulinemia and portal hypoinsulinemiahyperinsulinemia and portal hypoinsulinemia

(50% of insulin is degraded during the first pass)

– Hyperinsulinemia has been associated with:• The development of atherosclerosis, both directly

(stimulation of arterial smooth muscle growth) and indirectly (development of dyslipidemia and y ( p y phypertension).

• It has also been linked to increased conc. plasminogen activator inhibitor (PAI-1), which predisposes vessels to formation of lipid-laden rather than cell-rich plaques.

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Hyperinsulinemia has been associated with:I li i t lt f i d h ti• Insulin resistance as a result of increased hepatic glucose production, reduced postprandial peripheral glucose disposal, reduced insulin-stimulated glucose storage …..

• Downregulates insulin receptors and postreceptor pathways in the muscle and adipose tissues, thus causing insulin resistancecausing insulin resistance

• Hypertension, CVD, weight gain, and, in women, polycystic ovary syndrome


Portal hypoinsulinemia leads to lipoprotein abnormalities that lead to development andabnormalities that lead to development and progression of atherosclerosis.

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• A beneficial effect on pancreas graft tacceptance

(Hypothesis: antigen delivery via the portal vein favorably alters antigen presentation with subsequent induction of immunologic hyporeactivity and even tolerance)

More studies are needed to prove the immunologic advantage in favor of portal vein drainage

ObservationsObservations

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Pancreas Tx Volume

• Rates of pancreas transplantation have declined, despite improved pancreatic graft outcomes.

Pancreas Transplant Volume

Kandaswamy R et al; AJT 2013(13) [Suppl 1}:47-72

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Pancreas Tx Volume

• Fewer patients are placed on the waiting list

• Changes in the rate of diabetic nephropathy development

• Delayed progression of late-stage CKD

• Greater availability of better insulin-delivery tsystem

Pancreas Tx Volume (contin.)

• Better diabetes education

• Regional waiting list rules

• More stringent donor selection

• Greater scrutiny of center outcomes

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Acute RejectionAcute Rejection


Acute Rejection

• The incidence of rejection within 1-year post-transplantation in a cohort of 162 patients of all pancreas transplant types, including many re-transplants undergoing for-cause biopsies, was 21%, with antibody mediated rejection (AMR) acutewith antibody-mediated rejection (AMR), acute cellular rejection (ACR), and mixed rejection

occurring in nearly equal frequency

Neiderhaus, AJT 2013

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Acute Rejection

• In their study, the majority of pancreas rejection episodes were successfully reversed and graft function was maintained. However, 20% of grafts were lost within a year of diagnosis

Thi hi hli h h d f l di i d• This highlights the need for early diagnosis and efficient surveillance

Acute Rejection

• Rejection of the pancreas may be discordant with the kidney after SPK and there is a greater appreciationkidney after SPK and there is a greater appreciation of antibody-mediated rejection of the pancreas allograft

• De-novo donor-specific antibody without graft dysfunction remains an active area of study, and the treatment for this condition is uncleartreatment for this condition is unclear

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Acute Rejection

A ll f bi ll h• A pancreas allograft biopsy allows the surgeon to accurately identify and define rejection, and should be incorporated into the portfolio of pancreas transplant monitoring

Acute Rejection

O h li i l f j i• Other clinical parameters for rejection:

-hyperglycemia

-serum amylase/lipase

-C-peptide level

-hemoglobin A1C, or g ,

-(if bladder drained) urinary amylase

are insufficient because they are either too late or nonspecific

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Acute Rejection

Th ili d ff i f ill• The utility and cost–effectiveness of surveillance biopsies have not yet been studied

• Contrary to prior assumptions, concordance in pathology between kidney graft and pancreas graft biopsies after SPK transplantation is not 100% and grafts can exhibit differing types and degrees ofgrafts can exhibit differing types and degrees of rejection. Therefore, kidney biopsies alone for SPK patients are insufficient to determine the pathologic status of the pancreatic graft

Acute Rejection

Di d l b d d l ff bi• Discordant results between a duodenal cuff biopsy and pancreas parenchymal biopsy also occur

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Trends in Immunosuppression

Conclusion

• Pancreas Transplantation improves quality of life and life expectancy in uremic diabetic patientslife expectancy in uremic diabetic patients

• Improvement in surgical technique and rejection screening have made long-term outcome comparable to other organ transplants; kidney, liver, and heart

• Islet transplantation still holds promise for treatment of brittle diabetics

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Thank You

Pancreas Transplantation - Avera Health 1 Pancreas Transplantation Ahmad Bashar Abdulkarim, MD, PhD,...

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