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1 Current status of islet cell transplantation 성균관의대삼성서울병원 김재현

2 논의사항 췌도이식현황 췌도단독이식 (IA) vs. 신장이식후췌도이식 (IAK) or 신장췌도동시이식 (SIK) 1형당뇨환자의사망률 저혈당, 혈당불안정성에따른차이? 이식후의생존률증가? 신장 vs. 췌장 LDK vs. SPK vs. DDK 이식편 ( 신장 / 췌장 / 췌도 ) 생존률 신장이식후췌장 vs. 췌도이식비교 우리나라는어떤환자에게췌도이식을할것인가? 혈당불안정성, 저혈당위험평가방법 SPK vs. LDK +/- IAK? or SIK

3 췌도이식 (islet transplantation) 이란? Donor Pancreas Islet Isolation Islet Purification Islet Transplantation

4 Long term insulin independence rate in Edmonton Ryan EA at al. Diabetes 2005

5 Islet transplantation 성적 CITR 2008

6 High risk of sensitization after failed islet TPL Campbell et al. AJT % (22/81) 71% (10/14)

7 Islet Alone vs. IAK or SIK 장점 혈관합병증적다 대상환자가많다 단점 장기간면역억제제노출위험 ( 엄격한대상환자선정필요 ) Allosensitization 차후신장이식에영향? 장점 추가적인면역억제제노출없음 Islet alone 과성적비슷 혈관합병증많아서저혈당에의한사망률증가, 췌장이식보다췌도이식이안전 단점 대상환자가적다

8 SIK vs. SIK & IAK 인슐린중단 많은양의췌도혈당조절개선 췌도양과무관 Gerber et al. Diabetologia 2008

9 Current indications for islet cell transplantation Islet transplantation alone (ITA) Islet Alone 262 Patients with type 1 diabetes with no or minimal secondary complications in order to prevent severe hypoglycemia and diabetes complications 2007 CITR Does the risk of severe hypoglycemia justify an expensive procedure with life-long immunosuppression or jeopardizes the Islet After Kidney 30 outcome of a future kidney transplantation by sensitization? Islet after kidney (IAK) 2007 CITR 2008 CITR

10 Islet vs. Pancreas Transplantation Graft Survival

11 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 %/yr, 2%/20yrs T1DM 모든환자가동일?

12 The Causes of Sudden Death in UK Hypoglycemia Study (T1DM) International Diabetes Monitor Volume 21, Number 6, 2009

13 The Incidence of Severe Hypoglycemia in UK Hypoglycemia Study International Diabetes Monitor Volume 21, Number 6, 2009

14 Diabetes Care 26: , 2003

15 저혈당빈도 당뇨유병기간 저혈당관련사망 심혈관질환합병증 Diabetes Metab Res Rev 2008; 24:

16 T1DM mortality Kidney function Mortality: 10%/yr vs. 0.1~2%/yr Waiting-List Survival: S-Cr < 2.0 PTA Posttransplantation Survival PTA- 92%/4yr PAK- 88%/4yr SPK- 60%/4yr = 10%/yr PAK SPK PTA- 86%/4yr PAK- 85%/4yr SPK- 90%/4yr Waiting duration: 3.5yrs = 35% die >> If donor (+) for LDKT? 1995 ~2000 UNOS/OPTN, JAMA 2003

17 Mortality of T1DM Newly detected T1DM ~0.1%/yr T1DM with brittle & recurrent hypoglycemia 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

18 What is the best option for T1DMESRD with a live KT donor?

19 Unadjusted patient survival LDKT = SPKT > DDKT 2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

20 Adjusted patient survival LDKT > SPKT = DDKT 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 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

21 Unadjusted kidney graft survival LDKT = SPKT > DDKT 2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

22 Adjusted kidney graft survival LDKT > SPKT = DDKT 2000 ~2007 UNOS/OPTN, Clin J Am Soc Nephrol 2009

23 What is the best option for T1DMESRD? Surv vival Longer wait time = increased mortality SPK 50 10%/year 2~3%/year Years

24 Surv vival What is the best option for T1DMESRD? LDKT 2~3%/year Years

25 What is the best option for T1DMESRD? LDKT Surv vival Longer wait time for KT = increased mortality 10%/year 2~3%/year SPK Years

26 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?

27 T1DM mortality Pancreas TPL after KT Patient survival of KT alone 88% vs. PAK 85% Waiting-List Survival: S-Cr < 2.0 PTA Posttransplantation Survival PAK waiting = KT alone - 88%/4yr PAK SPK PAK- 85%/4yr 1995 ~2000 UNOS/OPTN, JAMA 2003

28 수술에따른위험 (SPK>KT) Treatment Days to equal risk Days to equal survival Dialysis (wait-listed) (reference) SPKT LDKT DDKT 43 95

29 췌장이식 : 제 1 형당뇨병말기신부전 (SPK, PAK) 반복되는저혈당 (PTA) (%) 100 췌장이식후췌장생존율 SPK PAK PTA (%) 100 췌장이식후환자생존율 SPK PAK PTA Post transplant months 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)

30 Reasons for early technical pancreas graft loss by duct management technique (USA primary pancreas transplants 1/1/2000 6/2004) 버려지는췌장 (80-90%) Variables SPK PAK PTA BD ED BD ED BD ED Graft Thrombosis 2.7% 5.4% 3.6% 6.1% 6.5% 8.0% 미국 (2005) UNOS data 한국 (2009)- KONOS data Infection 1.0% 1.3% 1.4% 1.4% 1.6% 1.8% 뇌사자수 Pancreatitis % 0.3% 뇌사자수 0.3% 0.1% % 0.0% 췌장 Anastomosis 이식수site 1438 leak 0.6% 1.3% 췌장 0.8% 이식수 1.5% % 2.1% 췌장이식대기자수 5276 췌장이식대기자수 373명 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

31 Objective scoring system? Diabetes 2004 Subjects: long standing T1DM 100 pts & islet TPL Mesurement: A composite hypoglycemic score (HYPO score) Lability index (LI) brittle Conclusion: 90 th percentile in T1DM, islet TPL pts (n=51) HYPO score: 1047, 1234 ± 184 LI: 433, (497, 330~692)

32 서울소재 5 개대학병원참가 Total: 124 (female 86, male 38) CVD:3 명 (2.4%) Nephropathy Overt proteinuria:18 명 (14.5%) Ccr<60: 10 명 8% Neuropathy: 14 명 (11.3%) Retinopathy:24 명 (19.4%) HTN: 23 명 (18.5%) Insulin regimen: MDI %

33 Candidate parameters Glycemic variability Using SMBG MAGE: Mean amplitude of glycemic excursion LI: lability index ADRR: average daily risk range SD: standard deviation Hypoglycemic unawareness HYPO score LBGI: low blood glucose index

34 (%) Results Total P <0.001 Glycemic variability Hypoglycemia 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 Duration of diabetes > 5 years Glycemic variability P <0.001 Hypoglycemia 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 Lability index:433 (35%) HYPO score:1,047 (0%)

35 저혈당위험성 = 당뇨유병기간 Brittle = c-peptide level N = 124 C-peptide (nmol/l) DM duration (year) SMBG number R P-value R P-value R P-value HbA 1C (%) ns ns <0.05 Glycemic variabi ility MAGE < ns ns ADRR < ns ns Lability index < ns <0.01 HBGI < ns ns Hypo LBGI ns < ns HYPO score ns < ns

36 결론 췌도이식 Islet alone: Brittle T1DM = 객관적평가척도필요 T1DMESRD: 면역억제제추가적위험없음 T1DMESRD 빠른신장이식이가장중요 LDK 가능하면빨리, 이후 IAK 고려 LDK 없으면 SPK SPK 가어려운고령, 심혈관질환동반 : DDK or SIK 고려 IAK vs. PAK 여부 LDK 이후저혈당, brittle 정도평가 c-peptide, 당뇨유병기간, 심혈관합병증 이식편기능 : PAK > IAK 시술관련위험성 : PAK> IAK

황지웅

황지웅 Comparison of Laparoscopy and Exploration in the Distal Pancreatectomy BACKGROUND: To determine the benefits of laparoscopic surgery compared with exploration, the clinical outcomes of open and laparoscopic