Current status of islet cell transplantationtransplantation

성균관의대 삼성서울병원김 재 현

논의 사항• 췌도이식 현황

– 췌도 단독이식 (IA) vs. 신장이식 후 췌도이식 (IAK) or 신장췌도 동시이식 (SIK)

• 1형 당뇨환자의 사망률– 저혈당, 혈당불안정성에 따른 차이 ?

이식 후의 생존률 증가? – 저혈당, 혈당불안정성에 따른 차이 ?– 이식 후의 생존률 증가?

• 신장 vs. 췌장• LDK vs. SPK vs. DDK

– 이식편 (신장/췌장/췌도) 생존률– 신장 이식후 췌장 vs. 췌도 이식 비교

• 우리나라는 어떤 환자에게 췌도 이식을 할 것인가 ?– 혈당불안정성, 저혈당 위험 평가 방법– SPK vs. LDK +/- IAK ? or SIK

췌도 이식 (islet transplantation) 이란?

Donor Pancreas

Islet IsolationIslet Isolation

Islet Purification Islet Transplantation

Ryan EA at al. Diabetes 2005

Long term insulin independence rate in Edmonton

Islet transplantation 성적

CITR 2008

High risk of sensitization after failed islet TPL

Campbell et al. AJT 2007

71%

(10/14)27%

(22/81)

Islet Alone vs. IAK or SIK

• 장점– 혈관합병증 적다– 대상환자가 많다

• 장점– 추가적인 면역억제제 노

출 없음– Islet alone과 성적 비슷– 혈관합병증 많아서 저혈• 단점

– 장기간 면역억제제 노출 위험 (엄격한 대상환자 선정 필요)

– Allosensitization – 차후 신장이식에 영향 ?

– 혈관합병증 많아서 저혈당에 의한 사망률 증가, 췌장이식보다 췌도이식이 안전

• 단점– 대상환자가 적다

인슐린 중단 – 많은 양의 췌도혈당 조절 개선 – 췌도 양과 무관

SIK vs. SIK & IAK

Gerber et al. Diabetologia 2008

Current indications for islet cell transplantation

• Islet transplantation alone (ITA)– Patients with type 1 diabetes with no or

minimal secondary complications in order to prevent severe hypoglycemia and diabetes complications

2007 CITR 2008 CITRcomplications – Does the risk of severe hypoglycemia justify

an expensive procedure with life-long immunosuppression or jeopardizes the outcome of a future kidney transplantation by sensitization ?

• Islet after kidney (IAK)

Islet Alone

262

Islet After Kidney

30

2007 CITR 2008 CITR

Islet vs. Pancreas TransplantationGraft Survival

Mortality of T1DM

• Individual diagnosed with T1DM today

faces an excess mortality over the next 20

years of ~2% or ~0.1%/yr

– ------------------ Khan MH, Diabetes Care 2009– ------------------ Khan MH, Diabetes Care 2009

– 0.1%/yr, 2%/20yrs

– T1DM 모든 환자가 동일 ?

The Causes of Sudden Death in UK

Hypoglycemia Study (T1DM)

International Diabetes Monitor Volume 21,

Number 6, 2009

The Incidence of Severe Hypoglycemia in

UK Hypoglycemia Study

International Diabetes Monitor Volume 21,

Number 6, 2009

Diabetes Care 26:1485–1489, 2003

저혈당 빈도∝ 당뇨 유병 기간저혈당 관련 사망∝심혈관 질환 합병증

Diabetes Metab Res Rev 2008; 24: 353–363

Waiting-List Survival: S-Cr < 2.0 Posttransplantation Survival

SPK

PAK

PTA- 92%/4yr

PAK- 88%/4yr

SPK- 60%/4yr = 10%/yr

T1DM mortality – Kidney functionMortality: 10%/yr vs. 0.1~2%/yr

PTA

PTA- 86%/4yr

PAK- 85%/4yr

SPK- 90%/4yr

1995 ~2000 UNOS/OPTN, JAMA 2003

SPK- 60%/4yr = 10%/yr

Waiting duration: 3.5yrs = 35% die

>> If donor (+) for LDKT ?

Mortality of T1DM

• Newly detected T1DM ~0.1%/yr

• T1DM with brittle & recurrent

hypoglycemia

– mortality 증가 2%/yr ~ 10%/yr (ESRD)– mortality 증가 2%/yr ~ 10%/yr (ESRD)

• Mortality of T1DM listed for a pancreas

TPL with S-Cr < 2.0 mg/dL: ~ 2.0%/yr

• Mortality of T1DMESRD: ~10%/yr

What is the best option for

T1DMESRD with a live KT

donor ?donor ?

Unadjusted patient survivalLDKT = SPKT > DDKT

2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

Adjusted patient survivalLDKT > SPKT = DDKT

2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

Despite more transplants from older donors

and among older recipients, LDKT was

associated with superior outcomes compared

with SPKT and was coupled with the least wait

time and dialysis exposure.

Unadjusted kidney graft survivalLDKT = SPKT > DDKT

2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

Adjusted kidney graft survivalLDKT > SPKT = DDKT

2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

What is the best option for

T1DMESRD ?

100

90

80

70

Survival

Longer wait time SPK

Years

70

60

50

40

Survival

1 2 3 4 5 6 7 8

10%/year 2~3%/year

Longer wait time

= increased mortality

SPK

What is the best option for

T1DMESRD ?

100

90

80

70

Survival

2~3%/year

LDKT

Years

70

60

50

40

Survival

1 2 3 4 5 6 7 8

What is the best option for

T1DMESRD ?

100

90

80

70

Survival

Longer wait time for

LDKT

Years

70

60

50

40

Survival

1 2 3 4 5 6 7 8

10%/year 2~3%/year

Longer wait time for

KT

= increased mortalitySPK

What is the best option for

T1DMESRD with a live KT donor ?

• Waiting time for SPK• Living donor for kidney transplantation

– If (+): LDKT consider as soon as possible– Brittle, recurrent hypoglycemia after KT or – Brittle, recurrent hypoglycemia after KT or

for quality of life >> IAK consider ? or PAK consider ?

Waiting-List Survival: S-Cr < 2.0 Posttransplantation Survival

SPK

PAK

PAK waiting = KT alone

- 88%/4yr

T1DM mortality – Pancreas TPL after KTPatient survival of KT alone 88% vs. PAK 85%

PTA

PAK- 85%/4yr

1995 ~2000 UNOS/OPTN, JAMA 2003

수술에 따른 위험 (SPK>KT)

Treatment Days to equal risk Days to equal survivalDialysis (wait-listed) (reference) SPKT 101 170LDKT 15 72DDKT 43 95LDKT 15 72DDKT 43 95

90

100

SPK PAK PTA

췌장 이식후 췌장 생존율(%)

90

100

SPK PAK PTA(%)

췌장 이식후 환자 생존율

췌장 이식: 제1형 당뇨병 말기신부전 (SPK, PAK) 반복되는 저혈당 (PTA)

50

60

70

80

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Post transplant months

70

80

90

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36

Post transplant months

SPK: simultaneous pancreas and kidney transplantation (1000 case/년) – Waiting List (3671)

PAK: pancreas transplantation after kidney transplantation (300 case/년)

PTA: pancreas transplantation alone (150 case/년) – Waiting List (1569)

Reasons for early technical pancreas graft loss

by duct management technique(USA primary pancreas transplants 1/1/2000–6/2004)

Variables SPK PAK PTA

BD ED BD ED BD ED

Graft Thrombosis 2.7% 5.4% 3.6% 6.1% 6.5% 8.0%

Infection 1.0% 1.3% 1.4% 1.4% 1.6% 1.8%

버려지는 췌장 (80-90%)

미국 (2005) – UNOS data 한국 (2009)- KONOS data 뇌사자수 7593 뇌사자수 256 Infection 1.0% 1.3% 1.4% 1.4% 1.6% 1.8%

Pancreatitis 0.4% 0.3% 0.3% 0.1% 1.6% 0.0%

Anastomosis site leak 0.6% 1.3% 0.8% 1.5% 0.0% 2.1%

Bleed 0.1% 0.5% 0.0% 0.5% 1.1% 1.7%

Total 4.8% 8.8% 6.1% 9.6% 10.8% 13.6%

BD: bladder drainage

ED: enteric drainage

SPK: simultaneous pancreas and kidney transplantation

PAK: pancreas transplantation after kidney transplantation

PTA: pancreas transplantation alone

뇌사자수 7593 뇌사자수 256 췌장 이식수 1438 췌장 이식수 22췌장이식 대기자수 5276 췌장이식 대기자수 373명

Objective scoring system ?

Diabetes 2004Diabetes 2004

Subjects: long standing T1DM 100 pts & islet TPL Mesurement:

A composite hypoglycemic score (HYPO score)Lability index (LI) – brittle

Conclusion: 90th percentile in T1DM, islet TPL pts (n=51)HYPO score: ≥1047, 1234 ± 184LI: ≥433, (497, 330~692)

서울 소재 5개 대학병원 참가

• Total: 124 (female 86, male 38)• CVD:3명(2.4%)• Nephropathy

– Overt proteinuria:18 명(14.5%) Ccr<60: 10명 8%– Overt proteinuria:18 명(14.5%) Ccr<60: 10명 8%

• Neuropathy: 14명 (11.3%)• Retinopathy:24명 (19.4%)• HTN: 23명(18.5%)• Insulin regimen: MDI - 84.2%

Candidate parameters

• Glycemic variability– Using SMBG

• MAGE: Mean amplitude of glycemic excursion• LI: lability index• LI: lability index• ADRR: average daily risk range• SD: standard deviation

• Hypoglycemic unawareness– HYPO score– LBGI: low blood glucose index

N=124 MAGE ADRR LI HBGI LBGI HYPO score

Median (lowest ~ highest)

115 (23 ~ 308) 33 (7 ~ 98) 359 (27~ 2125) 9 (1 ~ 53) 1.5 (0 ~ 8) 39 (0 ~ 949)

90 percentile 196 50 708 24 4.0 377

ResultsGlycemic variability HypoglycemiaTotal

P <0.001

(%)

Duration of diabetes > 5 years

N = 79 MAGE ADRR LI HBGI LBGI HYPO score

Median (lowest ~ highest)

131(33 ~308) 33 (9 ~99)323 (45 ~1726)

8.4 (2 ~36) 1.6 (0 ~8) 104 (0 ~429)

90 percentile 236 54 625 16.7 5.2 351

Lability index:433(35%)

Glycemic variability Hypoglycemia

HYPO score:1,047(0%)

P <0.001

저혈당 위험성 = 당뇨유병기간Brittle = c-peptide level

N = 124 C-peptide (nmol/l) DM duration (year) SMBG number

R P-value R P-value R P-value

HbA1C (%) 0.007 ns -0.069 ns -0.215 <0.05

MAGE -0.210 <0.05 0.044 ns -0.057 ns

variability

ADRR -0.312 <0.01 0.040 ns 0.076 ns

Lability index -0.269 <0.01 -0.096 ns 0.436 <0.01

HBGI -0.215 <0.05 0.009 ns -0.154 ns

LBGI -0.131 ns 0.184 <0.05 0.076 ns

HYPO score -0.148 ns 0.261 <0.01 0.042 ns

Glycemic

variability

Hypo

결론

• 췌도이식• Islet alone: Brittle T1DM = 객관적 평가 척도 필요• T1DMESRD: 면역억제제 추가적 위험 없음

• T1DMESRD – 빠른 신장이식이 가장 중요– 빠른 신장이식이 가장 중요

• LDK 가능하면 빨리, 이후 IAK 고려• LDK 없으면 SPK• SPK가 어려운 고령, 심혈관질환 동반: DDK or SIK 고려

– IAK vs. PAK 여부• LDK이후 저혈당, brittle 정도 평가

– c-peptide, 당뇨유병기간, 심혈관합병증• 이식편 기능: PAK > IAK• 시술관련 위험성: PAK> IAK