Simultaneous kidney pancreas transplant an option for type i and type ii diabetes

1. Hirohito Ichii MD, PhD, FACS
Professor of Clinical Surgery
Department of Surgery
University of California Irvine
Simultaneous Kidney / Pancreas Transplant
An option for Type I and Type II diabetes

2. No conflict of Interest
Disclosure

3. Objectives
 Indication
 Operation ( SPK )
 Immunosuppression
 Updated Management
 Clinical outcome (SPK for T2DM)
ESRD with DM send to UCI

4. Diabetes mellitus
Diabetes is a chronic problem in which blood glucose can no longer be
regulated.
Type 1 diabetes mellitus (T1DM) is an autoimmune disease associated
with selected genetic HLA alleles, which result in the permanent
destruction of beta-cells of the pancreatic islets of Langerhans
Type 2 diabetes is more common than T1DM.
Around 90 to 95 % of people with DM have T2 DM.
1. The body become resistant to insulin (insulin resistant).
2. Pancreatic beta-cells can't make enough insulin to keep up and begins
to fail (beta-cell exhaustion), due to cytokine-induced inflammation,
obesity and insulin resistance, and overconsumption of saturated fat
and free fatty acids (FFA).

5. Symptoms in DM

6. Insulin producing cells

7. Islets from cadaveric donor Islets from Type I diabetes patient

9. The Importance of Euglycemia

10. Diabetes Control and Complications Trial
(DCCT)
N. Engl. J. Med 1993; 329:977
 1460 Adults randomized to Conventional (1-2 doses insulin
daily) v.s. Intensive ( ≥ 3 doses insulin or insulin pump)
•Observed mean 6.5 years for complications
Retinopathy First Occurrence ↓ 76%
Progression ↓ 54%
Nephropathy Occurrence Microalbumiuri ↓ 39%
Clinical Albuminuria ↓ 54%
Neuropathy Progression ↓ 60%

11. 0%
2%
4%
6%
8%
10%
12%
1 2 3 4 5 6 7 8 9
Intensive
Conventional
Incidence of five or more episodes of
Hypoglycemia
Years

12. Treatment
1. Conventional
2. Multiple insulin injections daily (Intensive insulin therapy )
3. Continuous Subcutaneous Insulin Infusions (CSII)
Frequent monitoring of blood glucose
Risk of hypoglycemia
Insulin Therapy
Transplant
1. Pancreas Transplant
2. Islet cell Transplant

13. Potential Benefits:
No hypoglycemia
Normoglycemia
Insulin independence
No diet restriction
Prevention of complications
No limitation of daily
activities
Improvement in QOL
Potential Risks:
Procedure:
-Bleeding
-Thrombosis
Immunosuppression:
-Risk of infections, neoplasm
-Nephrotoxicity
-Neurotoxicity
-Beta Cell Toxicity
Transplantation vs. Insulin Therapy

14. Clinical Changes following Euglycemia
Associated with Pancreas Transplantation
Improvements in:
Cardiac Function.
Gaber AO, et al. Transplantation 1995;59(8):1105-1112.
Gaber AO, et al. Cell Transplantation 2000;9:913-918.
Diabetic Nephropathy.
Fioretto P, et al. N Engl J Med 1998; 339: 69-75.
Micro Angiopathy.
Perez RV. Transplantation 1999;68(7):927-932.
Autonomics/Gastric Function and Quality of Life.
Gaber AO. Transplantation 1994;57(6):816-822.

15. Pancreas transplant surgery

16. Remove the pancreas
Duodenum
Pancreas
Capsule
intact
Spleen
Liver still
in situ!

17. Back table preparation
.
Arterial Y-graft with Extension Preparation for islet trans[plant

18. SMA
Splenic Artery
Donor External
Iliac Artery
Donor Internal
Iliac Artery
Donor Common
Iliac Artery

19. Portal Vein
Iliac Artery Y Graft

20. Simultaneous Pancreas and Kidney Transplant (SPK)
Portal venous and Enteric DrainageSystemic venous and Bladder Drainage

21. Allograft Duodenum
Recipient Jejunum
Tail of Allograft Pancreas
SuperiorInferior

22. Systemic venous and Enteric drainage (head down)

23. Portal venous and Enteric Drainage (head up)

24. Immunosuppressive Protocol
1) Induction Ab:
a) Thymoglobulin: 1.0 - 1.5 mg/kg (IV) x 5 doses,
first dose intraoperative* usually QD
* Infused prior to reperfusion of pancreas or kidney
2) Tacrolimus: Oral dosing when creatinine <4 .0 mg/dl
Target Trough level 8-12 ng/ml
3) Steroid: Methylprednisolone 500 mg intraoperative*
tapered to 20 mg QD and then 5 mg QD by 1-2 months.
4) Myfortic : 720mg orally BID day 1 postoperative

25. Management of Immunosuppression
for SPK patients
Can we use kidney function to monitor
pancreas rejection?

26. Concurrent biopsies of both grafts in recipients of SPK
demonstrate high rates of discordance for rejection as well
as discordance in type of rejection – a retrospective study
Parajuli S Transpl Int. 2017 July 3
University of Wisconsin between 1/1/2001 and 12/31/2016,
Biopsy of both organs. 40 patients with SPK
25 (62.5%) patients: concordance of biopsy findings:
11 : rejection of both organs,
(4 out of 11: different types (AMR, ACR, or mixed) of rejection in the two organs)
14 : no rejection of either organ.
15 (37.5%) patients: discordant for rejection
10: pancreas-only rejection
5: kidney-only rejection.
This large series of simultaneous pancreas and kidney biopsies demonstrates the
continued utility of performing biopsies of both organs.

27. How can we detect recurrence of autoimmune
diabetes?
Management of Immunosuppression
for SPK patients

28. Recurrence of T1DM after SPK, despite immunosuppression, is
associated with autoantibodies and pathogenic autoreactive CD4 T-cells
Vendrame F et al. Diabetes 2010 Apr;59(4):947-57
3 case reports:
SPK transplant reversed DM. Pts returned to insulin dependence 5 – 9 years later,
while kidney and exocrine pancreas function remained unchanged.
Pts had GAD and IA-2 or ZnT8 autoantibodies before transplantation, which
persisted despite immunosuppression, and titers increased on follow-up
The pancreas biopsy showed insulitis.
Sorted the autoreactive potential of GAD-autoreactive CD4 T-cells from them.
Co-transplanted to diabetic nude mouse with human islets (1,300 IEQ), freshly
isolated from an unrelated, deceased donor
No reversal of DM. H&E staining revealed severe islet destruction in the graft

29. Management of thrombosis for SPK patients
How can we detect and treat thrombosis?

30. Splenic Vein Thrombosis Following Pancreas Transplantation:
Identification of Factors That Support Conservative Management
Harbell JW et al. AJT 2017 Nov;17(11):2955-2962.
112 recipients over a 5-year period at UCSF , evaluated by US.
30 recipients (27%): some degree of thrombus or absence of flow in the SV
5 /30 graft losses (4 due to venous thrombosis) within 20 days of transplant
All patients with non-occlusive partial SV thrombus but normal arterial signal were
successfully treated with IV heparin followed by warfarin for 3–6 months, and
remained insulin independent.
Findings of arterial signal abnormalities ( absence or reversal of diastolic flow )
require urgent operative intervention,
since this finding can be associated with more extensive thrombus that may lead to
graft loss.

31. Monitoring rejection and recurrence of autoimmune diabetes
Serum amylase and lipase levels
Fasting glucose levels
Ultrasound- guided biopsy
Auto-antibody level (GAD, IA-2, ZnT8)
Monitoring Early Thrombosis (2-8%)
Serum amylase and lipase levels
Fasting glucose levels
Duplex sonographic scanning of the allograft POD1
ASA 81-325 mg
Heparin drip
Monitoring Hemorrhage (5-10%) and Pancreatitis (auto-digestion)
Serum amylase and lipase levels
CBC
US and CT
Post-Transplant management for pancreas

32. Clinical outcomes

33. Over 33K transplants performed in 2016 for first time in US
SPK 2000-2007 900-1000/year 2014-2016 700-800/year
Panc alone 2000-2007 300- 400/year 2014-2016 200-250/year

35. SPK

36. Congreso Medico
Asistencial 2005
Ojo et al. Transplantation 2001; 71: 82-90.
Patient Survival
Type 1 diabetes
w/ ESRD
US National Cohort

37. Expected Lifetime - Type 1 DM w/ ESRD
8 Y
12.9 Y
23.4 Y
20.9 Y
Dialysis CAD SPK LKD
Ojo et al. Transplantation 2001; 71: 82-90.

38. Summary - Pancreas Transplantation for T1DM
Excellent long-term patient / graft survival
– Low technical complication
– Low infectious complication
– Low immunological graft loss
Better patient survival than kidney alone
– SPK = Living Kidney > Deceased Donor Kidney
Less secondary complications
– Particularly nephropathy and neuropathy
Better quality of life than Insulin therapy
– Less secondary complications
– Insulin independence

39. (Only Primary) deceased donor pancreas transplants for T2DM in IPTR/UNOS
between 1995 and 2015.
1514 for Type IIDM (out of 22,206)
SPK 1317 recipients (88%),
PAK 140 recipients (9 %)
PTA 50 recipients (3 %),
Islet 5 recipients,
(Pancreas re-transplants 33 cases)
Patient, pancreas, kidney graft survival rates increased significantly over time
Clinical outcomes primary deceased donor (DD) SPK patients with T2DM
between 1995 and 2015 by era
Gruessner et al. Curr Diab Rep (2017) 17: 44
Pancreas (SPK) at UCI: patient 100%, graft 100% at 3 years
Kidney alone at UCI: patient 92.2%, graft 87.6% at 3 years
SPK for DM at nation: patient 95.4%, graft 89.6% at 3 years
Kidney at nation: patient 93.6%, graft 88.5 % at 3 years
SPK for T2DM at nation: patient 95.8%, pancreas 83.3%, kidney 91.1% at 3 years

40. Patient survival.
Hazard ratios for patient death risk factors
(95% CI)
Clinical outcomes primary deceased donor (DD) SPK patients with T2DM
between 1995 and 2015 by era
Gruessner et al. Curr Diab Rep (2017) 17: 44
2009-2015
2002-2008
1995-2001

41. Pancreas graft function
Hazard ratios (95% CI)
for pancreas graft failure risk factors
Clinical outcomes primary deceased donor (DD) SPK patients with T2DM
between 1995 and 2015 by era
Gruessner et al. Curr Diab Rep (2017) 17: 44
2009-2015
2002-2008
1995-2001

42. Kidney graft function Hazard ratios (95% CI)
for kidney graft failure risk factors
Clinical outcomes primary deceased donor (DD) SPK patients with T2DM
between 1995 and 2015 by era
Gruessner et al. Curr Diab Rep (2017) 17: 44
2009-2015
2002-2008
1995-2001

43. Era (transplant year) 1995–2001 2002–2008 2009–2015 p value
Number of primary treatment (%) 298 (23) 482 (36) 542 (41) <0.0001
Recipient age [years] 44.5 (8.4) 47.8 (8.0 46.3 (8.2) <0.0001
Gender
Male 198 (66) 337 (70) 401 (74) 0.06
Race
White
Black
Hispanic
Multi/other
235 (79)
43 (14)
16 (5)
4 (2)
277 (57)
110 (23)
69 (14)
26 (6)
186 (34)
174 (32)
128 (23)
54 (11)
<0.0001
Body mass index [kg/m2]
<18.5 (underweight)
18.5–24.9 (normal)
25–29.9 (overweight)
≥30 (obese)
Missing
9 (3)
145 (51)
104 (37)
27 (9)
13
7 (1)
193 (41)
184 (39)
92 (19)
6
8 (1)
197 (36)
252 (47)
84 (16)
1
<0.0001
Duration of T2D [years] 22 (7) 21(8) 21(8) 0.43
Dialysis (%) 254 (85) 424 (88) 492 (91) 0.04
Time to treatment [days]
0–<30
30–<180
180–<360
360+
22 (7)
115 (39)
67 (23)
94 (32)
47 (10)
142 (30)
93 (19)
200 (41)
71 (13)
193 (36)
106 (19)
172 (32)
0.005
Characteristic for SPK patients with T2DM between 1995 and 2015

44. Transplant year 1995–2001 2002–2008 2009–2015 p value
Donor age [years]
<15
15–29
30–44
45–59
34 (12)
172 (58)
75 (25)
16 (5)
43 (9)
306 (63)
99 (21)
34 (7)
64 (12)
336 (62)
131 (24)
11 (2)
0.05
Preservation time [h]
0–<12
12–23
≥24
Missing
92 (39)
133 (56)
13 (5))
60
202 (54)
165 (44)
10 (2)
105
337 (66)
168 (33)
4 (1)
33
<0.0001
DCD donor 0 (0) 8 (2) 20 (4) 0.002
Donor cause of death
Trauma
CCV
CNS tumor
Missing
217 (74)
76 (26)
2 (0)
3
370 (77)
108 (22)
3 (1)
1
423 (79)
110 (21)
1 (0)
8
0.34
Body mass index [kg/m2]
<18.5 (underweight)
18.5–24.9 (normal)
25–29.9 (overweight)
≥ 30 (obese)
Missing
20 (7)
194 (66)
59 (20)
20 (7)
5
26 (5)
274 (57)
137 (29)
45 (9)
0
40 (7)
317 (58)
144 (27)
41 (8)
0
0.08
HLA A, B, DR MM
0
1
2
3
4
5
6
Missing
13 (4)
7 (2)
8 (3)
39 (13)
82 (28)
87 (30)
54 (19)
3
5 (1)
4 (1)
21 (4)
66 (14)
109 (23)
175 (36)
102 (21)
1
1 (0)
0 (0)
12 (2)
50 (9)
118 (22)
209 (39)
152 (28)
8
<0.0001
Deceased donor characteristic for SPK

45. Transplant year 1995–2001 2002–2008 2009–2015 p value
Treatment center volume
Low
Medium
Large
85 (28)
106 (36)
107 (36)
100 (21)
128 (26)
254 (53)
60 (11)
138 (25)
344 (63)
<0.0001
Duct management
Enteric drainage
Bladder drainage
189 (65)
98 (34)
387 (82)
79 (18)
494 (92)
42 (8)
<0.0001
Venous management
Systemic
Portal
128 (72)
50 (28)
309 (82)
69 (18)
349 (72)
139 (28)
0.005
Induction therapy
None
Non-depleting AB
Depleting AB
Both
Missing
132 (46)
50 (17)
106 (36)
7 (2)
3
131 (28)
39 (8)
289 (61)
12 (3)
11
73 (14)
15 (3)
440 (82)
8 (1)
6
<0.0001
Maintenance protocol
Tac&MMF
CsA&MMF
CsA&AZA
Tac alone
MMF alone
Srl based
Other
Missing
159 (55)
61 (21)
11 (4)
14 (5)
6 (2)
18 (6)
22 (7)
7
379 (81)
7 (1)
0 (0)
14 (3)
7 (2)
50 (11)
11 (2)
14
512 (95)
3 (1)
0 (0)
3 (1)
3 (1)
8 (1)
6 (1)
7
<0.0001
Steroid-free protocol
Yes
No
Missing
28 (9)
267 (91)
3
104 (22)
367 (78)
11
210 (39)
326 (61)
6
<0.0001
Transplant characteristic

46. Transplant year 1995–2001 2002–2008 2009–2015 p value
Technical failure
rate [%]
8.9 6.9 5.6 0.21
Graft
thrombosis [%]
5.0 4.7 3.0 0.26
Infection [%] 3.2 0.9 0.9 0.02
Pancreatitis [%] 0.0 0.9 0.4 0.23
Anastomotic
leak [%]
0.7 0.2 0.8 0.48
Bleeding [%] 0.0 0.2 0.4 0.57
Reasons for primary early technical failures

47. Summary
 SPK is a safe procedure with excellent pancreas and
kidney graft outcome in patients with T2DM.
 The procedure restores euglycemia and freedom from
insulin and dialysis.

48. Why do we offer SPK for T2DM patients at UCI?
• Longest waiting time for kidney in the US
(panc waiting time 1-1.5 years)
• Higher quality of donors (young age, low BMI,
shorter CIT)
• The better quality of recipients (shorter
dialysis and DM time, T2 <T1)
• No recurrence of autoimmune diabetes
• Not super competitive area for pancreas
transplant at this point
• Two ASTS certified transplant surgeons
• Prevention of poor glucose control post Tx
(IM, better renal function)
Rapamycin impairs in vivo
proliferation of islet beta-cells
Transplantation. 2007
Dec 27;84(12):1576-83

49. Intra-peritoneal glucose
tolerance test
after TAC 6W
(Glucose：2g/kg BW)
(mg/dL)
***
(mg/dL)
(min)
Serum Creatinine
after TAC 6w

50. 1. Age < 55 yr (ideally <50)
2. BMI < 32 kg/m2 (ideally <30)
3. Insulin dependence (total insulin requirements < 1 U/kg of
BW/day)
4. Fasting c-peptide < 10 ng/mL
5. Low cardiac and vascular disease risk
6. Presence of renal failure (dialysis dependent or pre-dialysis
advanced diabetic nephropathy with GFR ≤ 20.
7. History of medical and dietary compliance
8. No candidate for living donor
Our current criteria for SPK for T2DM patients with dialysis

51. ESRD with DM send to UCI
Thanks!