ORIGINAL DATA DIABETIC

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1 The Review of DIABETIC STUDIES Vol 14 No Secial IPITA Issue The Review of DIABETIC STUDIES ORIGINAL DATA Benefits of Islet Translantation as an Alternative to Pancreas Translantation: Retrosective Study of More Than 10 Ten Years of Exerience in a Single Center Barbora Voglová 1, Martina Zahradnická 1, Peter Girman 1, Jan Kríž 1, Zuzana Berková 1, Tomáš Koblas 1, Ema Vávrová 1, Lenka Németová 1, Lucie Kosinová 1, David Habart 1, Eva Fábryová 1, Eva Dovolilová 1, Ivan Leontovyc 1, Tomáš Neškudla 1, Jan Peregrin 2, Jozef Kovác 2, Kvetoslav Liár 3, Matej Kocík 3, Tomáš Marada 3, Jirí Svoboda 1, František Saudek 1 1 Deartment of Diabetes, Institute for Clinical and Exerimental Medicine, Prague, Czech Reublic. 2 Deartment of Diagnostic and Interventional Radiology, Institute for Clinical and Exerimental Medicine, Prague, Czech Reublic. 3 Deartment of Translant Surgery, Institute for Clinical and Exerimental Medicine, Prague, Czech Reublic. Address corresondence to: Frantisek Saudek, Frantisek.saudek@ikem.cz Manuscrit submitted June 6, 2017; acceted June 10, 2017 Abstract BACKGROUND: Pancreas translantation (PTx) reresents the method of choice in tye 1 diabetic atients with conservatively intractable hyoglycemia unawareness syndrome. In 2005, the Institute for Clinical and Exerimental Medicine (IKEM) launched a rogram to investigate the safety otential of islet translantation (ITx) in comarison to PTx. AIM: This study aims to comare the results of PTx and ITx regarding severe hyoglycemia elimination, metabolic control, and comlication rate. METHODS: We analyzed the results of 30 atients undergoing ITx and 49 atients treated with PTx. All atients were C-etide-negative and suffered from hyoglycemia unawareness syndrome. Patients in the ITx grou received a mean number of 12,349 (6,387-15,331) IEQ/kg/erson administered ercutaneously into the ortal vein under local anesthesia and radiological control. The islet number was reached by 1-3 alications, as needed. In both grous, we evaluated glycated hemoglobin, insulin dose, fasting and stimulated C-etide, frequency of severe hyoglycemia, and comlications. We used the Mann Whitney test, Wilcoxon signed-rank test, and aired t-test for analysis. We also individually assessed the ITx outcomes for 1. Introduction slet (ITx) and ancreas (PTx) translantation are the methods of choice in tye 1 diabetes atients suffering from conservatively intractable hyoglycemia unawareness syndrome caused each atient according to recently suggested criteria established at the EPITA meeting in Igls. RESULTS: Most of the reciients showed a significant imrovement in metabolic control one and two years after ITx, with a significant decrease in HbA1c, significant elevation of fasting and stimulated C-etide, and a markedly significant reduction in insulin dose and the frequency of severe hyoglycemia. Seventeen ercent of ITx reciients were temorarily insulinindeendent. The results in the PTx grou were comarable to those in the ITx grou, with 73% graft survival and insulin indeendence in year 1, 68% 2 years and 55% 5 years after translantation. There was a higher rate of comlications related to the rocedure in the PTx grou. Severe hyoglycemia was eliminated in the majority of both ITx and PTx reciients. CONCLUSION: This reort roves the successful initiation of ancreatic islet translantation in a center with a well-established PTx rogram. ITx has been shown to be the method of choice for hyoglycemia unawareness syndrome, and may be considered for alication in clinical ractice if conservative otions are exhausted. Keywords: tye 1 diabetes hyoglycemia unawareness syndrome islet translantation ancreas translantation by imaired hyoglycemia counter-regulatory mechanisms [1]. Both rocedures have been demonstrated to achieve elimination of severe hyoglycemia and recovery of the counter-regulatory resonse [2]. Further acknowledged benefits of ITx and PTx include the revention of the rogression 10 DOI /RDS

2 Benefits of Islet Translantation The Review of DIABETIC STUDIES 11 Abbreviations: BMI CGM EPITA GFR HbA1c IEQ IKEM ITx IU MAGE PTx of diabetes comlications (although this is not definitely roven in all studies) [3-6] and rotection of the renal graft against the harmful effect of hyerglycemia [7]. However, ongoing imrovements in islet isolation and translantation techniques, resulting in lower comlication rates and increased numbers of insulin-indeendent subjects [8, 9], may emhasize the advantage of ITx over PTx because of the greater risk of surgical comlications associated with PTx [10]. The aim of this retrosective study is to evaluate the results of the first ten years of clinical islet translantation in a single center with a wellestablished ancreas translantation rogram, and to comare the results between atients undergoing ITx and PTx regarding the frequency of severe hyoglycemia, insulin requirements, metabolic control indicators, and comlications. 2. Methods and atients 2.1 Islet translantation body mass index continuous subcutaneous glucose monitoring Euroean Pancreas and Islet Translant Association glomerular filtration rate glycated hemoglobin islet equivalents Institute for Clinical and Exerimental Medicine islet translantation insulin units mean amlitude of glycemic excursions ancreas translantation The islet translantation rogram in our center was initiated in November Since then, a total number of 62 atients have received islet translants, of whom: - 27 atients received ITx alone - 10 atients underwent simultaneous islet and kidney translantation - 5 atients underwent simultaneous islet and liver translantation - 8 atients received islets after kidney translantation - 12 atients received islet auto-translantation after total ancreatectomy In this study, we evaluated the results of 30 atients (15 men and 15 women) who received ITx alone (n = 24), islet after kidney translantation (n = 4), and simultaneous islet and kidney translantation (n = 2). Patients who received autotranslantation (12), those who underwent islet and liver translantation (5), and those not diagnosed with severe hyoglycemia unawareness syndrome were not included in the study. The translantations were erformed between January 2006 and March 2017 in atients who suffered from hyoglycemia unawareness and severe hyoglycemia, and who were statistically comarable to those atients after ancreas translantation alone. The atients included in this study had the following characteristics at baseline (median interquartile range, see Table 1): - Aged 48.5 (37-57) years - Undetectable C-etide - Diabetes duration 24 ( ) years - BMI 23.8 ( ) kg/m 2 The number of ITx treatments was as follows: - 11 atients received 3 ITx - 9 atients received 2 ITx - 10 atients received 1 ITx The mean number of translanted islets amounted to 12,349 (6,387-15,331) islet equivalents (IEQ)/kg/atient. At the time of the study, the follow-u times of the atients were as follows: - 16 atients had the last ITx more than 5 years ago - 8 atients had the last ITx 24 months ago - 6 atients had shorter follow-u eriods Two atients after ITx with a marginal islet graft function stoed immunosuression because of adverse effects and were lost to follow u after ITx for two years. Islets were isolated according to the modified Edmonton rotocol. Collagenase NB1 Premium (Serva) or CIzyme Collagenase HA (Vitacyte) was used [11, 12]. After urification, the tissue was collected and cultured for a maximum of 24 hours at 37 C. Islet infusion was administered under radiological control via transheatic access (ortal vein) or via laaroscoy. The immunosuression rotocol consisted of: - Induction with anti-t lymhocyte globulin (total dose 9 mg/kg, one dose re-translant and one dose at day one ost-translant) Rev Diabet Stud (2016) 14:10-21

3 12 The Review of DIABETIC STUDIES Voglová et al. - Methylrednisolone - One dose of etanercet (followed by maintenance treatment based on sirolimus and low-dose tacrolimus using the intention-to-treat aroach) Hearin and insulin were administered intravenously in the first 24 hours in accordance with reviously ublished rotocols [13]. Pancreas donors had a medium age of 49 (44-57) years and BMI 26 (24-29) kg/m 2. The most common cause of death was intracranial hemorrhage in 78%, and cold ischemia time was 4.5 ( ) hours. In our ITx reciients, we rosectively analyzed indicators of metabolic comensation (glycated hemoglobin, insulin requirements, frequency of severe hyoglycemia, and C-etide) and kidney function 1, 3, 6, 12, and 24 months after the last ITx (with the maximal islet-mass) and comlications. The frequency of severe hyoglycemia (accomanied by imaired consciousness or the need for another erson s assistance) according to the Clarke/Gold score used for hyoglycemia unawareness evaluation [14, 15] was followed u before, 12, and 24 months after ITx. Since 2013, we have enriched our follow-u investigation with mixed-meal stimulation test and continuous subcutaneous glycemia monitoring (CGM). Stimulated C-etide was measured after 120 minutes of a mixed-meal test containing 60 g saccharides, 12.5 g roteins, and 12.6 g liids. Patients with normal renal function were included for statistical evaluation only. Data are shown as median (interquartile range). Statistical analyses were erformed using the Wilcoxon-signed rank test and Mann-Whitney test (Table 2). When evaluating CGM (using a Dexcom sensor) we assessed the excursions of glycemia (MAGE) [16] and the ercentage of time sent in hyoglycemia (<3.5 mmol/l), normoglycemia ( mmol/l), and hyerglycemia (>7.2 mmol/l). MAGE was calculated as mean ± SD, and Wilcoxon signed-rank test was alied for statistical analyses. We reort these results as well, but they do not aly to the entire grou included in this study. Our rimary objective in the follow-u investigations was to find out how many atients achieved a comosite endoint 6 and 12 months after ITx consisting of: Table 1. Baseline characteristics of islet and ancreas reciients and donors Characteristic Islet translant reciients (n = 30) - Significantly detectable C-etide (level >0.2 nmol/l) - More than 30% daily insulin dose reduction - Absence of severe hyoglycemia (requiring another erson s assistance or hositalization) - Imroved metabolic control with HbA1c of 53 mmol/mol or less For the urose of this article, we decided to view our results in the light of the recently agreed criteria for islet graft function (2017 Igls IPITA worksho, not yet ublished, see section 3.3). 2.2 Pancreas translantation Pancreas translant reciients (n = 49) Sex 15 M / 15 F 22 M / 27 F Age (years) 48.5 (37-57) 39 (33-50) Duration of diabetes (years) 27.5 ( ) 24 ( ) BMI (kg/m²) ( ) 23,8 ( ) Insulin dose before Tx (IU/kg) 0.51 ( ) 0,53 ( ) Frequency of severe 6 (4-8) 3 (2-6) hyoglycemia/atient/year HbA1c before Tx (mmol/mol) 73.5 (65-87) 74 ( ) C-etide before Tx Undetectable Undetectable GFR (CKD-EPI) ml/s/1.73 m ( ) 1.31 ( ) Pancreas donor age 49 (44-57)* 36 ( )* Pancreas donor BMI 26 (24-29)** 23 (20-27)** Total dose of islet equivalents (IEQ/kg) Legend: * < 0.05, ** = ,349 (6,387-15,331) Between Aril 1996 and Aril 2017, 49 atients underwent PTx treatment in our center, all of whom were C-etide-negative and suffering from severe hyoglycemia. 36 atients received PTx alone (PTA), while in 13 atients PTx was erformed after kidney translantation (PAK) from a living or deceased donor. The study oulation consisted of 22 men and 27 women aged 39 (33-50) years with diabetes duration of 24 ( ) years (Table 1). Our surgical technique has been evolving throughout this time. In the first 19 atients (translanted ), the ancreatic graft was drained into the urinary bladder and laced extraeritoneally in the right iliac fossa. In 2004, enteric exocrine drainage with an extraeritoneal graft lacement was introduced and erformed in 14 atients of the followed grou. Since 2011, this technique was imroved further and, while main- - Rev Diabet Stud (2016) 14:10-21 Coyright by Lab & Life Press/SBDR

4 Benefits of Islet Translantation The Review of DIABETIC STUDIES 13 Table 2. Metabolic indicators in islet translant reciients Time after ITx HbA1c (mmol/mol) Insulin dose (IU/kg/day)* Fasting C- etide (nmol/l) GFR (ml/s/1.73 m 2 ) Severe hyoglycemia /atient /year 1 mo 52 (49 58) < ( ) < ( ) < ( ) mo 45 (42-49) < ( ) < ( ) < ( ) mo 49 (42-57) < ( ) < ( ) < ( ) mo 54 (44-53) < ( ) < ( ) < ( ) (0.8-2) mo 54 (52-71) < ( ) ( ) < ( ) (3-5) yr 58 (51-76) ( ) ( ) ( ) (0.25-4) Legend: *17% of atients after ITx were transiently insulin-indeendent. taining enteric exocrine drainage, the ancreatic graft is laced intraeritoneally and anastomosed with the ortal vein and common iliac artery. This rocedure was used in 16 atients. As for immunosuression regimen, induction was achieved by anti-t-lymhocyte globulin (4 mg/kg re-translant dose) and methylrednisolone in PTA reciients, while basiliximab was used in PAK reciients. Ongoing intention-to-treat immunosuression consisted of tacrolimus with mycohenolate mohetil and taered doses of corticosteroids within the first 6 weeks. The immunosuressive regimen used before 2004 and the surgical rocedures are described in detail by Girman and colleagues [17]. Pancreas donor medium age was 36 ( ) years and BMI 23 (20-27) kg/m 2. The most frequent cause of death was intracranial hemorrhage in 65% of donors, and cold ischemia time was 5.2 (4-6.5) hours. In PTA reciients, we retrosectively evaluated HbA1c, fasting C-etide, insulin requirements, frequency of severe hyoglycemia, and kidney function 12 and 24 months ost-translant and 5 years ost-translant along with atient and graft survival. We also assessed 120-minute stimulated C-etide by oral glucose tolerance test (OGTT) using 75 g glucose 12 and 24 months after PTx. Furthermore, we analyzed comlications of the translant rocedure. The data are resented as median (interquartile range). Wilcoxon-signed rank test and Mann-Whitney test were used for statistical analyses. 3. Results 3.1 Metabolic outcomes of islet translantation Patients on the waiting list for islet translantation were all C-etide-negative. Desite intensive clinical management they had very oor diabetes control, with HbA1c of 73.5 mmol/mol (65-87 mmol/mol) (median (interquartile range)) (Figure 1A), daily insulin dose of 0.51 IU/kg ( IU/kg) (Figure 1C), and with a frequency of severe hyoglycemia (requiring hel of other erson or leading to a loss of consciousness) of 6 (4-8)/atient/year (Table 1). In the first month after ITx, HbA1c decreased significantly to 52 (49-58) mmol/mol ( < ), fasting C-etide levels were 0.24 nmol/l ( nmol/l) ( < ), and insulin dose decreased to 0.3 IU/kg ( IU/kg) ( < ). Graft function further imroved at 3 months ost-translant (Figure 1A-C), with: - HbA1c 45 mmol/mol (42-49 mmol/mol) ( < ) - Fasting C-etide 0.22 nmol/l ( nmol/l) ( < ) - Stimulated C-etide 0.84 nmol/l ( nmol/l) - Insulin dose 0.29 IU/kg ( IU/kg) ( < ) The values characterizing graft function remained stable until 12 months after translantation: - HbA1c 54 mmol/mol (44-53 mmol/mol) ( < ) - Fasting C-etide 0.22 nmol/l ( nmol/l) ( < ) - Stimulated C-etide 0.88 nmol/l ( nmol/l) - Insulin dose 0.23 IU/kg ( IU/kg) ( < ) The frequency of severe hyoglycemia varied around 1 (1-2)/atient/year ( = ). The values also remained stable even at 2 years ost- Rev Diabet Stud (2016) 14:10-21

5 14 The Review of DIABETIC STUDIES Voglová et al. A B C D Figure 1. Glycemic control arameters and kidney function after islet transolantation. A: HbA1c in mmol/mol, comaring baseline, 1, 3, 6, 12, 24 months, and 5 years after ITx. B: Fasting C-etide levels in nmol/l at baseline, 1, 3, 6, 12, 24 months, and 5 years after ITx. C: Daily insulin dose in IU/kg at baseline, 1, 3, 6, 12, 24 months, and 5 years after ITx. D: Kidney function after ITx (egfr in ml/s/1.73m² at baseline, 1, 3, 6, 12, 24 months, and 5 years after ITx). translant with a small rise in insulin dose to 0.29 IU/kg ( IU/kg) ( = ). The frequency of severe hyoglycemia at 2 years ost-translant remained significantly lower than under retranslant conditions, i.e. 4 (3-5) ( = ), see Table 2 and Figures 1A-C. Six atients had undetectable C-etide levels, five of them because of early graft failure by the end of the third month, and one by the end of the first year osttranslant. 3.2 Comlications of islet translantation Bleeding was the most frequent serious comlication associated with the ITx rocedure, esecially in the initial years of the translant rogram. This comlication occurred in 10 atients (33%). In terms of imlantations, the comlication rate was 18% (11 of a total of 62 imlantations). In 8 (27%) of these atients, urgent oeration was necessary. Four atients (13%) develoed an intraheatic hematoma without the need for surgical rocedure and with favorable outcome. One atient develoed artial ortal vein thrombosis with the need for long-term anticoagulation theray. One atient had an orthostatic syncoe shortly after the translantation rocedure with the need for vasoressive medication. Biliary tract irritation was reorted in two atients. Rev Diabet Stud (2016) 14:10-21 Coyright by Lab & Life Press/SBDR

6 Benefits of Islet Translantation The Review of DIABETIC STUDIES 15 Figure 2. Evaluation of continuous glucose monitoring (CGM). The figure shows the change in time eriods atients sent in hyoglycemia (< 3.5 mmol/l, blue), normoglacemia ( mmol/l, green), and hyerglycemia (>7.2 mmol/l, red) after islet translantation (ITx). Regarding infectious comlications, one atient was imlanted with a graft infected by hemolytic E. Coli, resulting in severe sesis, but the atient recovered with no sequelae. One atient had cholecystitis, 3 atients were treated for urinary tract infections, and 1 atient acquired neumonia during hositalization after the translantation. Thrombocytoenia was resent in 4 atients, and leucoenia with neutroenia was observed in 10 cases, which was due to immunosuressive medication. We evaluated the continuous glucose monitoring (CGM) reorts and found that before ITx the atients had hyoglycemia in 4% ( %) of the measured time, normoglycemia in 42% (31-52%) of the time, and hyerglycemia in 54% (46-67%) of the time (Figure 2). These values imroved gradually over 6 months after ITx to yield: - Hyoglycemia 1% ( %) ( = ) - Normoglycemia 68% (48-71%) ( = ) - Hyerglycemia 31% (27-41%) ( = ) We also calculated the mean amlitude of glycemic excursion (MAGE) values. The values decreased gradually from 7.4 ± 3.9 mmol/l before ITx to 5.0 ± 0.8 mmol/l 6 months after ITx ( = ) (Figure 3). 3.3 Islet graft function according to 2017 Igls classification (Tables 3 and 4) As for the overall assessment of islet function, our rimary comosite endoint (C-etide >0.2 nmol/l, >30% daily insulin dose reduction, absence of severe hyoglycemia, HbA1c 53 mmol/mol) was achieved in 17 atients (60%) 6 months after ITx and in 14 atients (50%) 12 months after ITx. Two years after ITx, 10 atients (42%) still met the criteria. In relation to the Igls classification, no a- Rev Diabet Stud (2016) 14:10-21

7 16 The Review of DIABETIC STUDIES Voglová et al. tient fulfilled the definition of long-term otimal graft function with total insulin indeendence. This was achieved for a short eriod in five atients (17%) only. However, the criteria for good islet graft function and successful theray were met by 17 atients (57%) after 6 months, 13 atients (46%) after 12 months, and 9 atients 24 months ost-translant. In five atients (17%), the graft failed shortly after translantation, and in two more by the end of the second year ost-translant. In total, 29% of grafts failed by the end of year 2. Marginal, yet stable, graft function was maintained in 8 atients in year 2. In the extended retrosective follow-u, three atients exerienced good graft function until the end of the fifth year (16%), 10 had marginal islet function (56%), and 8 grafts failed (26%). In 17 atients (57%), hyoglycemia awareness was restored and has been maintained so far desite only marginal graft function in some atients. We observed a significant increase in C-etide levels and a decrease in HbA1c in the first two years after ITx. The frequency of severe hyoglycemia was significantly reduced, and exogenous insulin dose decreased substantially in the first year, with some atients being insulin-free for a limited eriod. In atients with at least marginal graft function, increased C-etide levels combined with lowered HbA1c and the reduction or absence of severe hyoglycemia ersisted two years after ITx. According to the CGM evaluation after translantation, hyoglycemia and hyerglycemia events significantly decreased, while eriods with otimal glucose levels increased. Lability of diabetes was also lower three and six months after ITx. 3.4 Metabolic outcomes, graft survival, and comlications of ancreas translantation Figure 3. Analyses of glycemic variability. Mean amlitude of glycemic excursions (MAGE) in mmol/l, mean values in atients before ITx, 1, 3, and 6 months after ITx. Candidates for PTx were C-etide-negative, had HbA1c of 75 mmol/mol (71-84 mmol/mol) (Table 1), and took a daily dose of insulin 0.6 IU/kg ( IU/kg). They were suffering from severe hyoglycemia with a frequency of 3 (2-6)/atient/year. One year after organ translantation, HbA1c decreased significantly to 37 mmol/mol (34-55 mmol/mol) ( < ), and 36 atients (73%) with functional ancreatic graft did not need insulin injections. (Table 5, Figures 4 and 5). Fasting and stimulated C-etide were 1.03 nmol/l ( nmol/l) and 1.96 nmol/l ( nmol/l), resectively. In eleven atients, graftectomy was erformed in the first-year osttranslant. Five atients lost their graft function because of acute cellular rejection. Eight atients (18%) had 2 (1-4) severe hyoglycemia eisodes/atient/year. All these atients originated from the grou with graft failure or exlanted graft. Two years after PTx, HbA1c was 38 mmol/mol (36-68 mmol/mol) ( < ), and 32 atients (68%) remained free from exogenous insulin. Fasting and stimulated C-etide were 0.79 nmol/l ( nmol/l) and 1.51 nmol/l ( nmol/l), resectively (Table 5). Seven atients (16%) suffered from severe hyoglycemia with 4 (2-5) eisodes/atient/year. Table 3. Classification of beta-cell graft function roosed at the IPITA worksho, EPITA Conference, Igls, 2017 Functional status HbA1c (%/ mmol/mol) Severe hyoglycaemia events Insulin requirements C-etide Success Otimal (1) 6.5 / 48 None No > Baseline Yes Good (2) < 7.0 / < 53 None < 50% Baseline > Baseline Yes Marginal (3) 7.0 / 53 < Baseline 50% Baseline > Baseline No Failure (4) Baseline Baseline Baseline Baseline No Rev Diabet Stud (2016) 14:10-21 Coyright by Lab & Life Press/SBDR

8 Benefits of Islet Translantation The Review of DIABETIC STUDIES 17 Table 4. Metabolic outcomes according to Igls criteria in translant reciients with normal renal function (1-24) and imaired renal function (25-30) in followed time intervals since the last islet translant No. 1-6 mo 6-12 mo mo Year 3 Year 4 Year *** *** Legend: For colors and numbers see Table 3. ***Patient stoed immunosuression theray and were temorarily lost to follow-u. + died 14 months after ITx. In the long term follow-u, the reciients renal function measured by glomerular filtration rate decreased significantly in the first two years osttranslant, but remained stable thereafter (Table 5, Figure 5). Acute rejection caused graft failure in eight cases, chronic allograft rejection was diagnosed in one atient, and in two atients the cause of failure remained unknown. Of the total number of 53 PTx (including retranslantations), eleven graftectomies (20%) took lace within the early osttranslant eriod. Four atients subsequently underwent re-translantation. Exlantation was erformed because of venous thrombosis (n = 6), infection (n = 2), bleeding (n = 2), and acute rejection (n = 1). Overall, surgical revision (including graftectomy) had to be erformed in 23 atients (47%); major causes were infection (n = 10) or bleeding (n = 6). When comaring the evolving surgical methods, we found that within the first eriod ( ) either graftectomy or re-oeration had been erformed in 9 of 19 atients (47%), and in the eriod in 8 of 14 atients (57%). Since 2011, surgical revision has been erformed in 6 of 16 atients (37%). In summary, in the first year of PTx, 73% of atients had good graft function without the need for exogenous insulin injections, 5% had artial function, and 22% exerienced graft failure or removal of the graft because of rejection or surgical comlications. In the second year of PTx, 68% of the reciients were still insulin-indeendent and 5-year graft survival was 55%. 47% of atients required surgical revision, most commonly due to thrombosis, infection, and/or bleeding. After the introduction of new surgical techniques with intraeritoneal graft lacement, there has been a decrease in the rate of comlications requiring re-oeration. 4. Discussion Our reorted results highlight the imortance of considering islet translantation as an alterna- Rev Diabet Stud (2016) 14:10-21

9 18 The Review of DIABETIC STUDIES Voglová et al. Table 5. Metabolic indicators in ancreas translant reciients Time after PTx HbA1c (mmol/mol) Patients free of insulin Fasting C- etide (nmol/l) GFR ml/s/1.73 m2 Severe hyoglycemia /atient /year 12 mo 38 (34-65) < % < ( ) < ( ) (1-4) in 18% 24 mo 38 (36-68) < % < ( ) < ( ) (2-5) in 16 % 5 yr 41 (36-65) < % < ( ) ( ) tive treatment otion in intractable hyoglycemia unawareness syndrome. It must be noted that this attemt was made in a center with extensive exerience and excellent results in ancreas translantation [17]. The study reflects the difficulties to be overcome at the beginning of a rogram before ancreatic islet translantation becomes an effective and safe treatment of hyoglycemia unawareness syndrome to attain stabilization of glucose metabolism in roerly selected atients. Achievement of long-term insulin-indeendence is the target. However, at resent, it does not reresent a rerequisite for the assessment of success. How can we interret the data and what lesson can we learn from it? In our islet translant grou, good metabolic control and elimination of severe hyoglycemic eisodes could be achieved in most of the reciients. Insulin theray could be stoed comletely in 5 out of 30 atients, and in most of the remaining atients the insulin dose was significantly reduced. Based on these results, ITx was aroved as a treatment modality for tye 1 diabetic atients suffering from the hyoglycemia unawareness by the Czech medical authorities and insurance roviders. Desite these achievements, we have not yet reached the level of insulinindeendence some leading centers in the world achieve [8, 9, 18-22]. The definition of a successful beta-cell theray still remains a challenge. Therefore, a set of criteria based on arameters of metabolic control (HbA1c and fasting C-etide), insulin dose, and resence of hyoglycemia was suggested at the meeting of the Euroean Pancreas and Islet Translant Association (EPITA) in 2017 held in Igls (Austria). In revious studies, our grou had used its own comosite endoints. In this study, we included the Igls criteria in addition (see Tables 3 and 4) to enable more effective comarison with other grous. When the newly introduced classification was used, our atients did not fit into the otimal function category. It is evident that overall translant success was evaluated in a similar way. Generally, there are several areas in need of imrovement. Islet isolation and donor allocation rocesses should be mentioned first and foremost. Besides imroving isolation techniques, we need to focus on thoughtful donor selection and the oten- A B Figure 4. Glycemic control arameters before and after PTx. A: HbA1c before and after ancreas translantation. B: Fasting C-etide before and after ancreas translantation. Rev Diabet Stud (2016) 14:10-21 Coyright by Lab & Life Press/SBDR

10 Benefits of Islet Translantation The Review of DIABETIC STUDIES 19 tial for enlarging the donor ool. As a very active ancreas translantation center, we are cometing with ourselves when it comes to suitable ancreas donors. The ancreas donors for islet translants were observed to be significantly older in our cohort (49 yr (44-57 yr) vs. 36 yr ( yr), < 0.05) and had significantly higher BMI (26 kg/m 2 (24-29 kg/m 2 ) vs. 23 kg/m 2 (20-27 kg/m 2 ), = ) than those assigned for organ translantation (Table 1). Our results suort the findings of Niclauss et al. who reorted better clinical outcomes of islet translantation from younger donors (<45 years) [23]. In relation to atient and graft survival, the outcome of our ancreas translant rogram is comarable to other centers. The rate of surgical comlications has decreased since the imlementation of new surgical technique. The assessment of clinical success in ancreas translantation is more straightforward and mainly based on insulin indeendence. In atients with a functioning ancreas graft, we have been able to achieve excellent long-term metabolic control, without the need for insulin theray and recurrence of severe hyoglycemia. Since islet translantation is a minimallyinvasive rocedure with fewer exected rocedurerelated risks, the initial translantations at our center, which were comlicated by bleeding, raised concerns about suitable safety measures. In 2013, we introduced fibrin glue (Avitene Collagen Hemostat, Davol, A Bard Comany, USA) which is laced into the intraheatic channel immediately after islet infusion. This has reduced the bleeding eisodes significantly. In the case of an exected increased risk of bleeding, we also considered the otion of using mini-laarotomy (a small incision) to ut the islet infusion straight into the inferior mesenteric vein similarly to the rocedures of simultaneous islet and kidney translantation. Comared to ercutaneous transheatic alication, this rocedure oses a low risk of bleeding into the abdominal cavity and of liver hematoma develoment [24]. Another issue to be determined concerns the selection of suitable candidates who would rofit from one or other theraeutic otion. The scale of modern technologies available is incomarable to the oortunities in the revious decades when we were launching the translant rogram. Therefore, we should be certain that all otions of conservative management are exhausted before considering ITx. It must be clear that the atient will benefit from the theray weighed against the burden of immunosuression. Figure 5. Kidney function before and after PTx. Until recently, there has also been a substantial difference in the health care and economic olicy in relation to these two rocedures. While ancreas translantation has been fully covered by health insurance, islet translantation had been considered an exerimental theray, and has been only artially funded. Islet isolation rocedures in articular needed to be suorted by research grants. The situation has imroved since 2016 when islet translantation was aroved as a theraeutic modality covered by insurance for indicated cases in the Czech Reublic. 5. Conclusions Islet and ancreas translantation have become established treatment modalities for tye 1 diabetes atients suffering from hyoglycemia unawareness and severe hyoglycemia when all means of conservative theray fail. We have comared retrosectively the long-term outcomes obtained with our ancreas and islet translant rogram. The results show that ancreas and islet translantation are not cometing theraies, but rather comlementary rocedures [25, 26]. The final decision for this theray should be made considering the overall health condition and comorbidities of the atient and the desired objectives, while the atient s references need to be acknowledged. Our results contributed to the areciation by national health authorities of islet translantation as a viable alternative to organ translantation. The availability of both PTx and ITx can significantly widen the number of diabetic Rev Diabet Stud (2016) 14:10-21

11 20 The Review of DIABETIC STUDIES Voglová et al. reciients rofiting from translantation of insulin-roducing tissue and imrove their health. Acknowledgments: The roject was suorted by the Czech Ministry of Health ( A) and the Institute for Clinical and Exerimental Medicine ( ). References 1. Choudhary P, Rickels MR, Senior PA, Vantyghem MC, Maffi P, Kay TW, Keymeulen B, Inagaki N, Saudek F, Lehmann R, Hering BJ. Evidence-informed clinical ractice recommendations for treatment of tye 1 diabetes comlicated by roblematic hyoglycemia. Diabetes Care : Rickels MR. Recovery of endocrine function after islet and ancreas translantation. Curr Diab Re : Fioretto P, Steffes MW, Sutherland DE, Goetz FC, Mauer M. Reversal of lesions of diabetic nehroathy after ancreas translantation. N Engl J Med : Kennedy WR, Navarro X, Goetz FC, Sutherland DE, Najarian JS. Effects of ancreatic translantation on diabetic neuroathy. N Engl J Med : Lee TC, Barshes NR, O'Mahony CA, Nguyen L, Brunicardi FC, Ricordi C, Alejandro R, Schock AP, Mote A, Goss JA. The effect of ancreatic islet translantation on rogression of diabetic retinoathy and neuroathy. Translant Proc : Boggi U, Vistoli F, Amorese G, Giannarelli R, Coelli A, Mariotti R, Rondinini L, Barsotti M, Piaggesi A, Tedeschi A, et al. Results of ancreas translantation alone with secial attention to native kidney function and roteinuria in tye 1 diabetes atients. Rev Diabet Stud : Kleinclauss F, Fauda M, Sutherland DE, Kleinclauss C, Gruessner RW, Matas AJ, Kasiske BL, Humar A, Kandaswamy R, Kaul S, et al. Pancreas after living donor kidney translants in diabetic atients: imact on long-term kidney graft function. Clin Translant : Hering BJ, Clarke WR, Bridges ND, Eggerman TL, Alejandro R, Bellin MD, Chaloner K, Czarniecki CW, Goldstein JS, Hunsicker LG, et al. Phase 3 Trial of Translantation of Human Islets in Tye 1 Diabetes Comlicated by Severe Hyoglycemia. Diabetes Care : Barton FB, Rickels MR, Alejandro R, Hering BJ, Wease S, Naziruddin B, Oberholzer J, Odorico JS, Garfinkel MR, Levy M, et al. Imrovement in outcomes of clinical islet translantation: Diabetes Care : Lehmann R, Graziano J, Brockmann J, Pfammatter T, Kron P, de Rougemont O, Mueller T, Zuellig RA, Sinas GA, Gerber PA. Glycemic Control in Simultaneous Islet-Kidney Versus Pancreas-Kidney Translantation in Tye 1 Diabetes: A Prosective 13-Year Follow-u. Diabetes Care : Shairo AM, Lakey JR, Ryan EA, Korbutt GS, Toth E, Warnock GL, Kneteman NM, Rajotte RV. Islet translantation in seven atients with tye 1 diabetes mellitus using a glucocorticoid-free immunosuressive regimen. N Engl J Med : Disclosures: The authors declare that the study was aroved by the local ethics committee. There is no conflict of interests in connection with the ublication of this article. The creation and ublication of this article were not suorted by the harmaceutical industry. This statement alies to all co-authors. 12. Saudek F, Girman P, Kriz J, Berkova Z, Zacharovova K, Koblas T, Pektorova L, Vavrova E, Mindlova M, Habart D, et al. Islet translantation for treatment of tye- 1 diabetes mellitus. Cas Lek Cesk : Koh A, Senior P, Salam A, Kin T, Imes S, Dinyari P, Malcolm A, Toso C, Nilsson B, Korsgren O, Shairo AM. Insulin-hearin infusions eritranslant substantially imrove single-donor clinical islet translant success. Translantation : Clarke WL, Cox DJ, Gonder-Frederick LA, Julian D, Schlundt D, Polonsky W. Reduced awareness of hyoglycemia in adults with IDDM. A rosective study of hyoglycemic frequency and associated symtoms. Diabetes Care : Gold AE, MacLeod KM, Frier BM. Frequency of severe hyoglycemia in atients with tye I diabetes with imaired awareness of hyoglycemia. Diabetes Care : Service FJ, Molnar GD, Rosevear JW, Ackerman E, Gatewood LC, Taylor WF. Mean amlitude of glycemic excursions, a measure of diabetic instability. 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12 Benefits of Islet Translantation The Review of DIABETIC STUDIES : Niclauss N, Meier R, Bedat B, Berishvili E, Berney T. Beta-Cell Relacement: Pancreas and Islet Cell Translantation. Endocr Dev : Moassesfar S, Masharani U, Frassetto LA, Szot GL, Tavakol M, Stock PG, Posselt AM. A Comarative Analysis of the Safety, Efficacy, and Cost of Islet Versus Pancreas Translantation in Nonuremic Patients With Tye 1 Diabetes. Am J Translant : Rev Diabet Stud (2016) 14:10-21