G Model
ARTICLE IN PRESS
YPHRS 2821 1–6
Pharmacological Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Clinical results of islet transplantation
1
Q1
2
Paola Maffi a , Antonio Secchi b,∗ a
3
b
4
Diabetes Research Institute, Internal Medicine and Transplant Unit, Scientific Institute San Raffaele, Milan, Italy Internal Medicine and Transplant Unit, Vita Salute University, Scientific Institute San Raffaele, Milan, Italy
5
6 18
a r t i c l e
i n f o
a b s t r a c t
7 8 9 10 11 12
Article history: Received 10 February 2015 Received in revised form 17 April 2015 Accepted 17 April 2015 Available online xxx
13
17
Keywords: Islet Hypoglycemia unawareness Insulin independence
19
1. Introduction
14 15 16
Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100–65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient. © 2015 Published by Elsevier Ltd.
Q2 20 21 22 23 24 25 26 27 28 29 30
Biological beta-cell replacement is the best rational approach in the treatment of type-1 diabetes (T1D). Good glycemic control with intensive insulin treatment is known to markedly decrease the incidence of chronic microvascular complications and cardiovascular morbidity in patients with T1D [1,2]. However, this treatment is difficult, expensive, and associated with an increased incidence of severe hypoglycemia, which is often accompanied by hypoglycemic unawareness [3], provoking considerable morbidity and, at times, mortality [4]. In order to restore pancreatic endocrine function, islet infusion has optimal results with minimal risk. It is now an effective
∗ Corresponding author at: Internal Medicine and Transplant Unit, Vita Salute University, Scientific Institute San Raffaele, Via Olgettina 60, Milan, Italy. Tel.: +39 02 26432805; fax: +39 02 26433790. E-mail address: [email protected] (A. Secchi).
alternative choice to whole-pancreas transplantation in clinical practice, and not only in trials. The evolution of the clinical outcome of islet transplantation took place during the last ten years following the experience of the Edmonton group, who transplanted islets alone in seven patients with T1D and obtained 100% insulin independence, a result that had never previously been achieved [5]. This trial became a milestone in the history of T1D therapy. Prior to this, islet transplantation was generally applied only when associated with kidney transplantation, and virtually never in clinical trials. Indications changed, and selection criteria were extended to include patients who did not need solid-organ transplant. Consequently, centers worldwide specifically dedicated their activity to islet transplantation in the clinical setting. Many protocols were developed with the aim to improve results linked to the various phases of the procedure, isolation, engraftment, and immunosuppression. Ten years after the proof-of-concept success of the Edmonton group, data published by the CITR, representing the most complete and standardized collection of information on islet transplantation in qualified centers, reported the efficacy and safety of outcome between 1999 and
http://dx.doi.org/10.1016/j.phrs.2015.04.010 1043-6618/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
G Model
51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
72
YPHRS 2821 1–6
ARTICLE IN PRESS
2
P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
2010 [6]. The overall improvement of results is summarized by CITR data showing the global increase of the rate and duration of insulin independence. This success was the starting point for further studies on the multiple factors influencing islet transplantation, from the laboratory technique to the various immunosuppressive protocols. Insulin independence is not the only primary endpoint of islet transplantation. One of the most important problems of T1D is the management of hypoglycemia, particularly when sensibility has been lost: this is the first advantage achieved after islet transplantation, often without the achievement of insulin independence. Furthermore, the presence of endogenous insulin secretion, C-peptide, and the normalization of glycated hemoglobin levels are fundamental to control the chronic complications of T1D: microvascular [7], macrovascular [8], peripheral neuropathy [9], cerebral metabolism [10]. Encouraging results need to be counter-balanced with unsolved issues related to islet production, long-term transplanted tissue survival, and the risks of immunosuppression. In this review, we analyze the current clinical data reported by the most active centers worldwide, and we also focus on unsolved problems and their possible solution. 2. Islet isolation
106
The first problem in the clinical application of islet transplantation is tissue availability. The story of islet isolation is well known: in 1988, Camillo Ricordi introduced a technique to improve the efficiency of isolation techniques, which resulted in high islet yields [11]. This technique became the gold standard for all centers working on islets, both in research and in clinical application. Various studies have attempted to single out the donor and procedural factors needed for the success of pancreatic islet isolation and clinical transplantation [12–15]. The following donor variables have been identified: donor age, BMI, metabolic condition, pancreas characteristics, cause of death, and cold ischemia time. Various procedural evaluations have been performed on processing times, pancreas preservation methods, digestion enzyme selection, and purification methods. The most frequently used primary outcome in these studies pertained to islet yield represented by total islet equivalent (IEQ) and IEQ/g of pancreas or IEQ/kg of recipient body weight. Recently, the CITR group reported a comprehensive analysis of clinical grade islet products from a total of 1017 isolations performed at CITR-participating North American, European and Australian centers [16]. They found a significant IEQ increase in those most recently infused, and that a higher transplanted islet mass was independently associated with the clinical outcome of the insulin independence rate. As regards the endless debate concerning collagenase, they observed clear yield differentiation with Liberase and NB1 that were negatively and positively correlated with the IEQ/particle ratio, respectively. No direct correlation between donor age and IEQ-based measures was found. The CITR database provided information on donor insulin treatment, which had not previously been considered as a clinical islet isolation variable. Correlation was found between insulin use and higher beta cell/kg recipient. This finding is supported by preclinical research, which suggests that insulin treatment can promote or maintain islet beta-cell mass in rodents [17,18].
107
3. Indications for islet transplantation
73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
whole-pancreas/kidney transplantation is considered too risky; the risk of re-transplantation when a pancreas is lost after simultaneous pancreas/kidney transplantation; the surgical unsuitability of a pancreas from a kidney donor; the recipient subsequently opts out of whole-pancreas transplantation. For patients that need immunosuppressive therapy, islet transplantation might improve glycemic control, with beneficial effects on both patient and graft survival [19]. The indications concerning islet transplantation alone (ITA) are based on the clinical data produced by pancreas transplantation. In 2006 the American Diabetes Association stated the following specific criteria for pancreas and islet transplantation: (1) a history of frequent, acute, and severe metabolic complications (hypoglycemia, marked hyperglycemia, ketoacidosis) requiring medical attention; (2) clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; and (3) consistent failure of insulin-based management to prevent acute complications [20]. All centers with great experience in ITA underline the importance of hypoglycemic unawareness, which is one of the most dangerous complications of intensive insulin therapy and is considered the main criteria of patients eligibility for islet transplantation. It is has been shown that severe hypoglycemia depends mainly on the absence of residual insulin secretion, regardless of treatment intensity [21], and that the risk of death at five years is increased 3.4-fold in diabetic patients who report severe hypoglycemia [22]. Exclusion criteria are similar to those for all types of transplant, particularly chronic infective disease, a history of cancer, and psychiatric diseases. 4. Islet transplant procedure The standard method for islet transplantation is intraportal infusion through percutaneous catheterization of a peripheral portal branch with ultrasound guidance, or by surgical catheterization of a small mesenteric vein. The combined ultrasound and fluoroscopyguided technique is considered the safest procedural method, with a low complication rate [23]. Two/three islet infusions from multiple donors are typically required for each transplanted patient, although many recent trials have focused on the possibility of a single infusion. New perspectives in identifying alternative sites for islet infusion were provided in a pilot study, where the feasibility and safety of bone marrow were demonstrated in four patients who underwent islet autotransplantation after total pancreatectomy [24]. 5. Results of clinical trials To understand the volume of islet transplant activity, we have to refer to CITR reports (Fig. 1). Islet transplant clinical activity data have been collected since 1999 by the CITR, supported by the Juvenile Diabetes Research Foundation (JDRF), using results from the USA, Canada, and several centers in Europe and Australia comprising 81% of all allogeneic islet transplants conducted as clinical trials or standard of care. Six hundred seventy-seven recipients of allogeneic islet transplantation, 575 islets alone, 110 islets with kidney, were reported in 2010 [6]. 5.1. Metabolic data
108 109 110 111
The indications for islet rather than whole-pancreas transplantation in patients undergoing simultaneous or later kidney transplantation are well documented. They include: recipient suffers from major cardiovascular disease; when simultaneous
In all studies, function of the transplanted islets is studied in terms of: C-peptide secretion (basal and after stimulus), glycated hemoglobin values, and insulin independence. Following transplantation, the absence of further episodes of hypoglycemic unawareness is always reported, and is included in the primary
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140
141
142 143 144 145 146 147 148 149 150 151 152 153 154
155
156 157 158 159 160 161 162 163 164
165
166 167 168 169 170
G Model YPHRS 2821 1–6
ARTICLE IN PRESS P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
3
Fig. 1. A. Rates of insulin independence after allogeneic islet infusion (islet transplant alone and IAK), annually after last infusion by era (P = 0.02). B. Durability of graft function (basal C-peptide >0.3 ng/mL) after the last infusion, by era (P < 0.001). The immediate drop at time 0 is occurrences of primary nonfunction (i.e., C-peptide never >0.3 ng/mL). Modified from: Barton F et al., Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010 Diabetes Care, 2012. C. NAA/Cho (D) was significantly lower in individuals with T1D on the waiting list (T1DWL) compared with controls, whereas it was near-normal in patients undergoing ITA. D. The Cho-to-Cr ratio was increased in the T1D-WL group compared with both the ITA and CTRL groups, suggesting an increase in degenerative processes (P = 0.01). Modified from D’Addio F et al. Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes. Diabetes Care 2014;37:267–276. 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
endpoints as it is strictly correlated with basal graft function, even when insulin therapy is maintained. In fact, the transplanted islets play a role not only in endogenous insulin secretion but also in glucose counter-regulation. It has been shown that the epinephrine response improves, and endogenous glucose production is restored, with significant normalization of autonomic symptoms contrasting insulin-induced hypoglycemia [25,26]. The overview from the CITR report clearly demonstrates the improved metabolic results in recent times. A significant increase in the rate of insulin independence was seen during the 2007–2010 period: 66% were insulin-independent at one year, 55% at two years, and 44% at three years. From 1999 to 2002, 51% were insulin independent at one year, falling to 36% at two years, and to 27% at three years (P = 0.01). The durability of islet graft function, as measured by fasting C-peptide >0.3 ng/mL, improved significantly during the latter period: the lost of function expressed by the survival curve is almost 10% at four years. These data represent the summary of overall activity. However, single center performance shows interesting results. Some elegant studies underline the value of immunosuppressive and peri-transplant therapy. Bellin et al. provide remarkable data from the Minnesota group on single-donor islet transplantation success in a clinical series of islet transplant recipients, where T-cell depletion induction therapy with ATG was carried out, combined with intensive peri-islet
transplant management, based on the use of tumor necrosis factoralpha inhibition (TNF-␣-I, etanercept). Insulin independence was attained in five of the six recipients at one year; four recipients continued to be insulin-independent at a mean of 3.4 ± 0.8 years post-transplant [27]. A larger study carried out by the same group later confirmed that patients receiving potent induction immunosuppression, with FcR non-binding anti-CD3, or either ATG or alemtuzumab with etanercept, are more than twice as likely to maintain long-term insulin independence for ≥5 years posttransplant compared to those receiving IL-2 receptor antagonists, despite the fact that only a single-donor pancreas was utilized in over 70% of group 1 recipients. Insulin independence rates in these recipients approach those seen in whole-pancreas transplantation [28]. The authors speculated that potent immunosuppressive therapy targets T cells while preserving or expanding regulatory T cells and their function, minimizing cytokine toxicity on transplanted islets. Consequently, the islets can be protected from alloand auto-immune reactions [29–31]. Etanercept might mediate the benefit with two proposed mechanisms: preventing the detrimental effects of cytokine exposure at the time of islet infusion [32]; having a sustained impact on auto-immunity, as shown in animal models at diabetes onset [33]. A prospective trial showed that the addition of exenatide and etanercept to the standard Edmonton protocol (University of Illinois Chicago protocol) is associated with a significantly lower number of islets initially required
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220
G Model
221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268
269
270 271 272 273
274 275 276 277 278 279 280 281 282
YPHRS 2821 1–6
ARTICLE IN PRESS
4
P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
to achieve insulin independence, which was maintained for 15 months [34]. Sixty per cent of these patients were still not carrying out insulin therapy five years later [35]. Exenatide was also used in another study where patients showed chronic islet allograft dysfunction: exogenous insulin was significantly reduced with stable glycemic control [36]. The rationale of exenatide in islet transplantation was based on its metabolic effects: decreased gastric emptying, increased satiety, suppression of glucagon secretion, increased glucose-dependent insulin secretion, and increased peripheral sensitivity to insulin, as previously demonstrated in type-2 diabetes [37]. The hypothesis of its protective effect on islet survival, as demonstrated in preclinical models, has also changed [38]. Recently, the update of the clinical activity performed in Edmonton highlighted the role of some factors that determine success following single-donor islet infusion. Significant factors were: recipient age, insulin requirement at baseline, donor weight, donor BMI, islet transplant mass, and peri-transplant heparin and insulin administration [39]. These results confirm the role of engraftment on long-term transplanted islet survival, and specific strategies during the perioperative period become essential. Primary graft function was seen to be an important parameter of long-term islet transplant outcome. In a study where a consistent mass of islets was transplanted (2 or 3 infusions, mean 12,479 IE/kg) over a period of 90 days, optimal primary graft function (PGF) was associated with prolonged graft survival and better metabolic control: 8 out of 9 patients with optimal PGF maintained insulin independence at two years, compared to 1 out of 5 with suboptimal PGF [40]. The long-term survival of transplanted islets is currently a matter of debate. The Geneva group reported the longest duration of insulin independence: in a case report of islet after kidney transplantation in an insulin-independent patient with excellent metabolic function, who died of cerebral hemorrhage, they demonstrated intrahepatic survival of allogeneic islets of Langerhans for more than 13 years [41]. Insulin immune fluorescence staining demonstrated the absence of insulin-positive cells within the native pancreatic islets, together with the presence of insulinpositive islets in the liver with significant reshaping, discarding the notion that insulin-independence was achieved as a result of native -cell regeneration [42]. Most importantly, ITA was strongly associated with posttransplant rather than pre-transplant behavioral changes and worries linked to hypoglycemia [43]. When rigorous assessment of health-related quality of life (HRQL) is used, ITA patients show better HRQL at one year, although some resume insulin therapy, which indicates the beneficial impact of islet transplantation on glycemic brittleness, independent of poor tolerance to insulin injections [44]. 5.2. Effects on the chronic complications of diabetes The studies focused on the chronic complications of type-1 diabetes in patients who underwent islet transplantation, and how it influenced micro- and macrovascular complications, peripheral neuropathy, and the central nervous system. 5.2.1. Macroangiopathy – cardiovascular complications At our Institute, diabetic complication follow-up of patients receiving islet and kidney transplant was compared with that of type-1 diabetes patients receiving a kidney transplant alone [8]: the islet and kidney group showed improved cardiac function in terms of better diastolic function, QT dispersion, and reduced intima media thickness progression. Patients in the islet-kidney group attained HbA1c values similar to those found to prevent diabetic vascular complications in the Diabetes Control and Complications
Trial [45] and restoration of C-peptide secretion, even if they were not at all insulin independent. Better patient survival, fewer fatal cardiovascular events, and improved endothelial function were observed in a cohort of patients with long-term transplanted islet function plus kidney, compared to patients who had islets that did not function for more than 12 months. This difference did not correlate with glycated hemoglobin levels, but with C-peptide secretion and lower exogenous insulin requirement [46]. 5.2.2. Microangiopathy–retinopathy, nephropathy Color Doppler imaging showed an early increase in retinal arterial and venous blood flow velocities at one year after islet transplantation [47]. More recently, a crossover study [7] demonstrated that there was no progression of diabetic retinopathy and a slower progression of nephropathy after ITA than with intensive medical therapy. Some authors reported that diabetic nephropathy improved after replacement of metabolic control with transplant. First the effects of pancreas alone were clearly demonstrated at biopsies showing the reversion of diabetic nephropathy lesions 10 years after the pancreas transplant [48]. In studies on islet and kidney transplantation, although the pancreatic endocrine function was partially restored, improvement in renal function and kidney graft life span was demonstrated, probably on the base of increased activity in Na/K-ATPase in red blood cells and increased expression of Na/K-ATPase immunoreactivity in tubular cells of the transplanted kidney [49] or on the base of improved NOS expression in the kidney vascular function [50] supported by the partial restoration of C-peptide secretion. Recently, Lehmann et al. demonstrated no difference in the decline of kidney function for more than 10 years comparing patients who received SPK/PAK with SIK/IAK, although glycated hemoglobin was slightly lower and insulin independence rate higher in pancreas than in islet recipients [51]. 5.2.3. Peripheral and central nervous system complications The findings on peripheral neuropathy of the above cited study [7], evaluated by nerve conduction velocity (NCV), did not show significant differences between ITA and patients treated with intensive medical therapy. On the other hand, a longitudinal study based on nerve conduction velocity index, which is not limited by specific intra-individual variability for each nerve trunk, demonstrated an improvement after four and six years in patients receiving an islet and kidney transplant, and not in patients receiving only kidney [9]. Finally, it is important to mention Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy of proton findings on brain metabolism before and after islet transplantation: higher NAA-toCho (N-acetylaspartate to choline, a marker of neuronal density and function) and lower Cho-to-Cr (choline to creatine) ratio values in patients undergoing ITA (Fig. 1C and D), indicating a relative sparing of neuronal function from tissue degeneration and loss. Furthermore, a significant improvement was recorded in mood profile, depression and anxiety, speed of information processing, and attention abilities, with greater maintenance of neuropsychological attitude in islet-transplanted patients compared to those with T1D [10]. 5.3. Complications of islet transplantation A low incidence of complications correlated with the islet transplantation procedure was reported. The percutaneous intrahepatic infusion of islets, with combined ultrasound and fluoroscopic guidance, is considered the safest method. It allows a single puncture attempt in nearly 90% of cases [24], and the significant advantage of an early assessment of
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
283 284 285 286 287 288 289 290 291
292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315
316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337
338
339 340 341 342 343 344
G Model YPHRS 2821 1–6
ARTICLE IN PRESS P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378
379
380 381 382 383 384 385 386 387 388 389 390
391
bleeding at the end of the procedure. In a larger Edmonton study (278 procedures), 3.7% of cases developed partial portal thrombosis (no cases of complete thrombosis) that resolved within a few weeks with anticoagulation therapy. The packed cell volume >5 mL was highlighted as a risk factor [48,52]. The main concerns in ITA are immunological. Two issues need to be considered: immunosuppressive therapy and allo-autoimmune responses. Severe adverse events of immunosuppression in ITA were not reported. Regarding infection, CMV disease was rarely reported (sieroconversion 6/121; viremia 8/121) [53], and the incidence was lower than in pancreas transplant alone [54]. No post-transplant lymphoproliferative diseases were registered. Occasional solid cancer was described, but not in committed studies. The development of allo- and autoimmune responses after islet transplantation has also to be included in the list of complications. Preformed alloreactive antibodies are an important negative predictor of islet transplant outcome [55]; while preformed pre-transplant autoimmune antibodies only weakly predict post-transplant outcome [56]. In a large study, 46% of recipients underwent important post-transplant donor specific antibodies (DSA) increase; 37% showed an increase or serum conversion of autoantibodies (GADA, IA-2A, ZnT8A), and these findings were almost always associated with a direct decline in islet graft function [53,57]. The possible appearance of allo-antibodies, which could reduce the potential success not only of further islet transplant but also of subsequent solid organ transplant, particularly kidney, have to be considered in the risk/benefit balance. Finally it is important to outline the long-term effects of the immunosuppressive drugs on kidney function. Diabetic nephropathy, clinically diagnosed before the islet transplant, could get worse, while normal function was demonstrated to be well maintained. From this experience the criteria of inclusion for islet transplant alone should be conditioned by renal function [58]. 6. Conclusions Islet transplantation is a well-established treatment for brittle type-1 diabetes, and is specifically indicated when hypoglycemic unawareness is not compatible with daily life. Many clinical trials are under investigation in order to improve the results of long-term graft survival, to expand quality and mass tissue, and to modify the immunological response for tolerance induction. The results are comparable with whole pancreas transplantation in the absence of surgical and infective complications. The final balance of the benefits (no hypoglycemic unawareness, normal glucose control) risks (immunosuppression, sensitization) ratio has always to be taken into account when a patient is recruited for islet transplantation. Acknowledgements
393
The authors wish to thank Michael John for the English language editing of this manuscript.
394
References
392
395 396 397 398 399 400 401 402 403 404 405
[1] The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus, N. Engl. J. Med. 353 (1993) 329–986. [2] D.M. Nathan, P.A. Cleary, J.Y. Backlund, S.M. Genuth, J.M. Lachin, T.J. Orchard, et al., Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes, N. Engl. J. Med. 353 (2005) 2643–2653. [3] P.E. Cryer, Hypoglycemia is the limiting factor in the management of diabetes, Diabetes Metab. Res. Rev. 15 (1999) 42–46.
5
[4] E.R. Seaquist, J. Anderson, B. Childs, P. Cryer, S. Dagogo-Jack, L. Fish, et al., Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society, Diabetes Care 36 (2013) 1384–1395. [5] A.M. Shapiro, J.R. Lakey, E.A. Ryan, G.S. Korbutt, E. Toth, G.L. Warnock, et al., Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen, N. Engl. J. Med. 343 (4) (2000) 230–238. [6] F.B. Barton, M.R. Rickels, R. Alejandro, B.J. Hering, S. Wease, B. Naziruddin, et al., Improvement in outcomes of clinical islet transplantation: 1999–2010, Diabetes Care 35 (2012) 1436–1445. [7] D.M. Thompson, M. Meloche, Z. Ao, B. Paty, P. Keown, R.J. Shapiro, et al., Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy, Transplantation 91 (3) (2011) 373–378. [8] P. Fiorina, C. Gremizzi, P. Maffi, R. Caldara, D. Tavano, L. Monti, et al., Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients, Diabetes Care 28 (2005) 1358–1365. [9] U. Del Carro, P. Fiorina, S. Amadio, L. De Toni Franceschini, A. Petrelli, S. Menini, et al., Evaluation of polineuropathy markers in type 1 diabetic kidneytransplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis, Diabetes Care 30 (12) (2007) 3063–3069. [10] F. D’Addio, P. Maffi, P. Vezzulli, A. Vergani, A. Mello, R. Bassi, et al., Islet transplantation stabilizes hemostatic abnormalities and cerebral metabolism in individuals with type 1 diabetes, Diabetes Care 37 (2014) 267–276. [11] C. Ricordi, P.E. Lacy, E.H. Finke, B.J. Olack, D.W. Scharp, Automated method for isolation of human pancreatic islets, Diabetes 37 (4) (1988) 413–420. [12] R. Nano, B. Clissi, R. Melzi, G. Calori, P. Maffi, B. Antonioli, et al., Islet isolation for allotransplantation: variables associated with successful islet yield and graft function, Diabetologia 48 (2005) 906–912. [13] G.M. Ponte, A. Pileggi, S. Messinger, A. Alejandro, H. Ichii, D.A. Baidal, et al., Toward maximizing the success rates of human islet isolation: Influence of donor and isolation factors, Cell Transplant. 16 (2007) 595–607. [14] N. Niclauss, D. Bosco, P. Morel, S. Demuylder-Mischler, C. Brault, L. MilliatGuittard, et al., Influence of donor age on islet isolation and transplantation outcome, Transplantation 91 (2011) 360–366. [15] D.E. Hilling, E. Bouwman, O.T. Terpstra, P.J. Marang-van de Mheen, Effects of donor-, pancreas-, and isolation-related variables on human islet isolation outcome: a systematic review, Cell Transplant. 23 (2014) 921–928. [16] A.N. Balamurugan, B. Naziruddin, A. Lockridge, M. Tiwari, G. Loganathan, M. Takita, et al., Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR), 1999–2010, Am. J. Transplant. 14 (2014) 2595–2606. [17] J. Movassat, C. Saulnier, B. Portha, Insulin administration enhances growth of the beta-cell mass in streptozotocin-treated newborn rats, Diabetes 46 (1997) 1445–1452. [18] T. Kitamura, J. Nakae, Y. Kitamura, Y. Kido, W.H. Biggs III, C.V. Wright, et al., The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth, J. Clin. Investig. 110 (2002) 1839–1847. [19] F. Bertuzzi, C. Ricordi, Beta-cell replacement in immunosuppressed recipients: old and new clinical indications, Acta Diabetol. 44 (2007) 171–176, http://dx. doi.org/10.1007/s00592-007-0020-20-20-20 [20] American Diabetes Association, Pancreas and islet transplantation in type 1 diabetes, Diabetes Care 29 (4) (2006) 935. [21] The DCCT Research Group, Hypoglycemia in the Diabetes Control and Complications Trial, Diabetes 46 (1997) 271–286. [22] R.G. McCoy, H.K. Van Houten, J.Y. Ziegenfuss, N.D. Shah, R.A. Wermers, S.A. Smith, Increased mortality of patients with diabetes reporting severe hypoglycemia, Diabetes Care 35 (2012) 1897–1901. [23] M. Venturini, E. Angeli, P. Maffi, P. Fiorina, F. Bertuzzi, M.V. Salvioni, et al., Technique complications and therapeutic efficacy of percutaneous transplantation of human pancreatic islet cells in type 1 diabetes: the role of US, Radiology 234 (2) (2005) 617–624. [24] P. Maffi, G. Balzano, M. Ponzoni, R. Nano, V. Sordi, R. Melzi, A. Mercalli, M. Scavini, A. Esposito, et al., Autologous pancreatic islet transplantation in human bone marrow, Diabetes 62 (2013) 3523–3531. [25] M.R. Rickels, C. Fuller, C. Dalton-Bakes, E. Markmann, M. Palanjian, K. Cullison, et al., Restoration of glucose counterregulation by islet transplantation in longstanding type 1 diabetes, Diabetes (2014) 141620. [26] M. Ang, C. Meyer, M.D. Brendel, R.G. Bretzel, T. Linn, Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes, Diabetologia 57 (2014) 623–632. [27] M.D. Bellin, R. Kandaswamy, J. Parkey, H.J. Zhang, B. Liu, S.H. Ihm, et al., Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes, Am. J. Transplant. 8 (11) (2008) 2463–2470. [28] M.D. Bellin, F.B. Barton, A. Heitman, J.V. Harmon, R. Kandaswamy, A.N. Balamurugan, et al., Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes, Am. J. Transplant. 12 (6) (2012) 1576–1583. [29] P. Monti, M. Scirpoli, P. Maffi, N. Ghidoli, F. De Taddeo, F. Bertuzzi, et al., Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells, J. Clin. Invest. 118 (2008) 1806–1814. [30] B. Keymeulen, E. Vandemeulebroucke, A.G. Ziegler, C. Mathieu, L. Kaufman, G. Hale, et al., Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes, N. Engl. J. Med. 352 (2005) 2598–2608.
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491
G Model
492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539
YPHRS 2821 1–6
ARTICLE IN PRESS
6
P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
[31] K.C. Herold, S. Gitelman, C. Greenbaum, J. Puck, W. Hagopian, P. Gottlieb, et al., Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years, Clin. Immunol. 132 (2009) 166–173. [32] A. Rabinovitch, W. Sumoski, R.V. Rajotte, G.L. Warnock, Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture, J. Clin. Endocrinol. Metab. 71 (1990) 152–156. [33] X.D. Yang, R. Tisch, S.M. Singer, Z.A. Cao, R.S. Liblau, R.D. Schreiber, et al., Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice: I. The early development of autoimmunity and the diabetogenic process, J. Exp. Med. 180 (1994) 995–1004. [34] A. Gangemi, P. Salehi, B. Hatipoglu, J. Martellotto, Barbaro, J.B. Kuechle, et al., Islet transplantation for brittle type 1 diabetes: the UIC protocol, Am. J. Transplant. 8 (2008) 1250–1261. [35] M. Qi, K. Kinzer, K.K. Danielson, J. Martellotto, B. Barbaro, Y. Wang, et al., Fiveyear follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience, Acta Diabetol. 51 (5) (2014) 833–843. [36] T. Froud, R.N. Faradji, A. Pileggi, S. Messinger, D.A. Baidal, G.M. Ponte, et al., The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy and metabolic effects, Transplantation 86 (1) (2008) 36–45. [37] R.A. DeFronzo, R.E. Ratner, J. Han, D.D. Kim, M.S. Fineman, A.D. Baron, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes, Diabetes Care 28 (5) (2005) 1092–1100. [38] Y. Li, T. Hansotia, B. Yusta, F. Ris, P.A. Halban, D.J. Drucker, Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis, J. Biol. Chem. 278 (1) (2003) 471–478. [39] D.P. Al-Adra, R.S. Gill, S. Imes, D. O’Gorman, T. Kin, S.J. Axford, et al., Single-donor islet transplantation and long-term insulin independence in select patients with type 1 diabetes mellitus, Transplantation 98 (9) (2014) 1007–1012. [40] M.C. Vantyghem, J. Kerr-Conte, L. Arnalsteen, G. Sergent, F. Defrance, V. Gmyr, et al., Primary graft function, metabolic control and graft survival after islet transplantation, Diabetes Care 32 (2009) 1473–1478. [41] Y.D. Muller, S. Gupta, P. Morel, S. Borot, F. Bettens, M.E. Truchetet, et al., Transplanted human pancreatic islets after long-term insulin independence, Am. J. Transplant. 13 (2013) 1093–1097. [42] H.A. Keenan, J.K. Sun, J. Levine, A. Doria, L.P. Aiello, G. Eisenbarth, et al., Residual insulin production and pancreatic -cell turnover after 50 years of diabetes: Joslin Medalist Study, Diabetes 59 (2010) 2846–2853. [43] D.M. Radosevich, R. Jevne, M. Bellin, R. Kandaswamy, D.E.R. Sutherland, B.J. Hering, Comprehensive health assessment and five-yr follow-up of allogeneic islet transplant recipients, Clin. Transplant. 27 (2013) E715–E724. [44] P.Y. Benhamou, L. Milliat-Guittard, A. Wojtusciszyn, L. Kessler, C. Toso, R. Baertschiger, et al., on behalf of the GRAGIL group. Quality of life after islet transplantation: data from the GRAGIL 1 and 2 trials, Diabet. Med. 26 (2009) 617–621. [45] Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long term
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
complications in insulin-dependent mellitus, N. Engl. J. Med. 329 (1993) 977–986. P. Fiorina, F. Folli, F. Bertuzzi, P. Maffi, G. Finzi, M. Venturini, et al., Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients, Diabetes Care 26 (2003) 1129–1136. M. Venturini, P. Fiorina, P. Maffi, C. Losio, A. Vergani, A. Secchi, et al., Early increase of retinal arterial and venous blood flow velocities at color Doppler imaging in brittle type 1 diabetes after islet transplant alone, Transplantation 81 (2006) 1274–1277. P. Fioretto, M.W. Steffes, D.E. Sutherland, F.C. Goetz, M. Mauer, Reversal of lesions of diabetic nephropathy after pancreas transplantation, N. Engl. J. Med. 339 (2) (1998) 69–75. P. Fiorina, F. Folli, P. Zerbini, P. Maffi, C. Gremizzi, V. Di Carlo, et al., Islet transplantation is associated with improvement of renal function among uremic patients with type 1 diabetes mellitus and kidney transplants, J. Am. Soc. Nephrol. 14 (8) (2003) 2150–2158. P. Fiorina, M. Venturini, F. Folli, C. Losio, P. Maffi, C. Placidi, et al., Natural history of kidney graft survival, hypertrophy, and vascular function in end stage renal disease type 1 diabetic kidney transplanted patients: beneficial impact of pancreas and successful islet cotransplantation, Diabetes Care 28 (6) (2005) 1303–1310. R. Lehmann, J. Graziano, J. Brockmann, T. Pfammatter, P. Kron, O. de Rougemont, et al., Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation in type 1 diabetes: a prospective 13-year follow-up, Diabetes Q3 Care (2015). T. Kawahara, T. Kin, S. Kashkoush, B. Gala-Lopez, D.L. Bigam, N.M. Kneteman, et al., Portal vein thrombosis is a potentially preventable complication in clinical islet transplantation, Am. J. Transplant. 11 (2011) 2700–2707. B.L. Gala-Lopez, P.A. Senior, A. Koh, S.M. Kashkoush, T. Kawahara, T. Kin, A. Humar, A.M. Shapiro, Late cytomegalovirus transmission and impact of T-depletion in clinical islet transplantation, Am. J. Transplant. 11 (2011) 2708–2714. P. Maffi, M. Scavini, C. Socci, L. Piemonti, R. Caldara, C. Gremizzi, et al., Risks and benefits of transplantation in the cure of type 1 diabetes: whole pancreas versus islet, Rev. Diabet. Stud. 8 (1) (2011) 44–50. P.M. Campbell, A. Salam, E.A. Ryan, P. Senior, B.W. Paty, D. Bigam, et al., Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation, Am. J. Transplant. 7 (2007) 1242–1248. E. Bosi, S. Braghi, P. Maffi, M. Scirpoli, F. Bertuzzi, G. Pozza, et al., Autoantibody response to islet transplantation in type 1 diabetes, Diabetes 50 (2001) 2464–2471. L. Piemonti, M.J. Everly, P. Maffi, M. Scavini, F. Poli, R. Nano, et al., Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes, Diabetes 62 (5) (2013) 1656–1664. P. Maffi, F. Bertuzzi, F. De Taddeo, P. Magistretti, R. Nano, P. Fiorina, et al., Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy, Diabetes Care 30 (5) (2007) 1150–1155.
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588
ARTICLE IN PRESS
YPHRS 2821 1–6
Pharmacological Research xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Pharmacological Research journal homepage: www.elsevier.com/locate/yphrs
Clinical results of islet transplantation
1
Q1
2
Paola Maffi a , Antonio Secchi b,∗ a
3
b
4
Diabetes Research Institute, Internal Medicine and Transplant Unit, Scientific Institute San Raffaele, Milan, Italy Internal Medicine and Transplant Unit, Vita Salute University, Scientific Institute San Raffaele, Milan, Italy
5
6 18
a r t i c l e
i n f o
a b s t r a c t
7 8 9 10 11 12
Article history: Received 10 February 2015 Received in revised form 17 April 2015 Accepted 17 April 2015 Available online xxx
13
17
Keywords: Islet Hypoglycemia unawareness Insulin independence
19
1. Introduction
14 15 16
Islet transplantation is considered an advanced therapy in the treatment of type-1 diabetes, with a progressive improvement of clinical results as seen in the Collaborative Islet Transplant Registry (CITR) report. It is an accepted method for the stabilization of frequent hypoglycemia, or severe glycemic lability, in patients with hypoglycemic unawareness, poor diabetic control, or a resistance to intensive insulin-based therapies. Worldwide data confirm a positive trend in this field, with the integrated management of pivotal factors: adequate islet mass, immunosuppressive protocols, additional anti-inflammatory therapy, and pre-transplant allo-immunity assessment. Insulin independence has been observed in several clinical trials with different rate, ranging 100–65% of patients; the maintenance of this condition during the follow-up progressively decreased, actually arranged on 44% 3 years after the last infusion, according to data reported from the CITR. Successful duration is progressively increasing, with ≥13 years being the longest reported insulin-free condition on record. The immediate results of functioning islet transplantation are an improvement in hypoglycemic awareness and a reduction in the glycated hemoglobin level. Furthermore, many studies have shown its influence on the chronic complications of diabetes, such as peripheral neuropathy, retinopathy, and macroangiopathy. Pre-transplant nephropathy remains an exclusion criterion as immunosuppressive therapy can exacerbate kidney-function deterioration. The problems linked to immunosuppression following islet transplantation for the treatment of type-1 diabetes need to be considered in order to achieve the correct risk/benefit ratio for each patient. © 2015 Published by Elsevier Ltd.
Q2 20 21 22 23 24 25 26 27 28 29 30
Biological beta-cell replacement is the best rational approach in the treatment of type-1 diabetes (T1D). Good glycemic control with intensive insulin treatment is known to markedly decrease the incidence of chronic microvascular complications and cardiovascular morbidity in patients with T1D [1,2]. However, this treatment is difficult, expensive, and associated with an increased incidence of severe hypoglycemia, which is often accompanied by hypoglycemic unawareness [3], provoking considerable morbidity and, at times, mortality [4]. In order to restore pancreatic endocrine function, islet infusion has optimal results with minimal risk. It is now an effective
∗ Corresponding author at: Internal Medicine and Transplant Unit, Vita Salute University, Scientific Institute San Raffaele, Via Olgettina 60, Milan, Italy. Tel.: +39 02 26432805; fax: +39 02 26433790. E-mail address: [email protected] (A. Secchi).
alternative choice to whole-pancreas transplantation in clinical practice, and not only in trials. The evolution of the clinical outcome of islet transplantation took place during the last ten years following the experience of the Edmonton group, who transplanted islets alone in seven patients with T1D and obtained 100% insulin independence, a result that had never previously been achieved [5]. This trial became a milestone in the history of T1D therapy. Prior to this, islet transplantation was generally applied only when associated with kidney transplantation, and virtually never in clinical trials. Indications changed, and selection criteria were extended to include patients who did not need solid-organ transplant. Consequently, centers worldwide specifically dedicated their activity to islet transplantation in the clinical setting. Many protocols were developed with the aim to improve results linked to the various phases of the procedure, isolation, engraftment, and immunosuppression. Ten years after the proof-of-concept success of the Edmonton group, data published by the CITR, representing the most complete and standardized collection of information on islet transplantation in qualified centers, reported the efficacy and safety of outcome between 1999 and
http://dx.doi.org/10.1016/j.phrs.2015.04.010 1043-6618/© 2015 Published by Elsevier Ltd.
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50
G Model
51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71
72
YPHRS 2821 1–6
ARTICLE IN PRESS
2
P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
2010 [6]. The overall improvement of results is summarized by CITR data showing the global increase of the rate and duration of insulin independence. This success was the starting point for further studies on the multiple factors influencing islet transplantation, from the laboratory technique to the various immunosuppressive protocols. Insulin independence is not the only primary endpoint of islet transplantation. One of the most important problems of T1D is the management of hypoglycemia, particularly when sensibility has been lost: this is the first advantage achieved after islet transplantation, often without the achievement of insulin independence. Furthermore, the presence of endogenous insulin secretion, C-peptide, and the normalization of glycated hemoglobin levels are fundamental to control the chronic complications of T1D: microvascular [7], macrovascular [8], peripheral neuropathy [9], cerebral metabolism [10]. Encouraging results need to be counter-balanced with unsolved issues related to islet production, long-term transplanted tissue survival, and the risks of immunosuppression. In this review, we analyze the current clinical data reported by the most active centers worldwide, and we also focus on unsolved problems and their possible solution. 2. Islet isolation
106
The first problem in the clinical application of islet transplantation is tissue availability. The story of islet isolation is well known: in 1988, Camillo Ricordi introduced a technique to improve the efficiency of isolation techniques, which resulted in high islet yields [11]. This technique became the gold standard for all centers working on islets, both in research and in clinical application. Various studies have attempted to single out the donor and procedural factors needed for the success of pancreatic islet isolation and clinical transplantation [12–15]. The following donor variables have been identified: donor age, BMI, metabolic condition, pancreas characteristics, cause of death, and cold ischemia time. Various procedural evaluations have been performed on processing times, pancreas preservation methods, digestion enzyme selection, and purification methods. The most frequently used primary outcome in these studies pertained to islet yield represented by total islet equivalent (IEQ) and IEQ/g of pancreas or IEQ/kg of recipient body weight. Recently, the CITR group reported a comprehensive analysis of clinical grade islet products from a total of 1017 isolations performed at CITR-participating North American, European and Australian centers [16]. They found a significant IEQ increase in those most recently infused, and that a higher transplanted islet mass was independently associated with the clinical outcome of the insulin independence rate. As regards the endless debate concerning collagenase, they observed clear yield differentiation with Liberase and NB1 that were negatively and positively correlated with the IEQ/particle ratio, respectively. No direct correlation between donor age and IEQ-based measures was found. The CITR database provided information on donor insulin treatment, which had not previously been considered as a clinical islet isolation variable. Correlation was found between insulin use and higher beta cell/kg recipient. This finding is supported by preclinical research, which suggests that insulin treatment can promote or maintain islet beta-cell mass in rodents [17,18].
107
3. Indications for islet transplantation
73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105
whole-pancreas/kidney transplantation is considered too risky; the risk of re-transplantation when a pancreas is lost after simultaneous pancreas/kidney transplantation; the surgical unsuitability of a pancreas from a kidney donor; the recipient subsequently opts out of whole-pancreas transplantation. For patients that need immunosuppressive therapy, islet transplantation might improve glycemic control, with beneficial effects on both patient and graft survival [19]. The indications concerning islet transplantation alone (ITA) are based on the clinical data produced by pancreas transplantation. In 2006 the American Diabetes Association stated the following specific criteria for pancreas and islet transplantation: (1) a history of frequent, acute, and severe metabolic complications (hypoglycemia, marked hyperglycemia, ketoacidosis) requiring medical attention; (2) clinical and emotional problems with exogenous insulin therapy that are so severe as to be incapacitating; and (3) consistent failure of insulin-based management to prevent acute complications [20]. All centers with great experience in ITA underline the importance of hypoglycemic unawareness, which is one of the most dangerous complications of intensive insulin therapy and is considered the main criteria of patients eligibility for islet transplantation. It is has been shown that severe hypoglycemia depends mainly on the absence of residual insulin secretion, regardless of treatment intensity [21], and that the risk of death at five years is increased 3.4-fold in diabetic patients who report severe hypoglycemia [22]. Exclusion criteria are similar to those for all types of transplant, particularly chronic infective disease, a history of cancer, and psychiatric diseases. 4. Islet transplant procedure The standard method for islet transplantation is intraportal infusion through percutaneous catheterization of a peripheral portal branch with ultrasound guidance, or by surgical catheterization of a small mesenteric vein. The combined ultrasound and fluoroscopyguided technique is considered the safest procedural method, with a low complication rate [23]. Two/three islet infusions from multiple donors are typically required for each transplanted patient, although many recent trials have focused on the possibility of a single infusion. New perspectives in identifying alternative sites for islet infusion were provided in a pilot study, where the feasibility and safety of bone marrow were demonstrated in four patients who underwent islet autotransplantation after total pancreatectomy [24]. 5. Results of clinical trials To understand the volume of islet transplant activity, we have to refer to CITR reports (Fig. 1). Islet transplant clinical activity data have been collected since 1999 by the CITR, supported by the Juvenile Diabetes Research Foundation (JDRF), using results from the USA, Canada, and several centers in Europe and Australia comprising 81% of all allogeneic islet transplants conducted as clinical trials or standard of care. Six hundred seventy-seven recipients of allogeneic islet transplantation, 575 islets alone, 110 islets with kidney, were reported in 2010 [6]. 5.1. Metabolic data
108 109 110 111
The indications for islet rather than whole-pancreas transplantation in patients undergoing simultaneous or later kidney transplantation are well documented. They include: recipient suffers from major cardiovascular disease; when simultaneous
In all studies, function of the transplanted islets is studied in terms of: C-peptide secretion (basal and after stimulus), glycated hemoglobin values, and insulin independence. Following transplantation, the absence of further episodes of hypoglycemic unawareness is always reported, and is included in the primary
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140
141
142 143 144 145 146 147 148 149 150 151 152 153 154
155
156 157 158 159 160 161 162 163 164
165
166 167 168 169 170
G Model YPHRS 2821 1–6
ARTICLE IN PRESS P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
3
Fig. 1. A. Rates of insulin independence after allogeneic islet infusion (islet transplant alone and IAK), annually after last infusion by era (P = 0.02). B. Durability of graft function (basal C-peptide >0.3 ng/mL) after the last infusion, by era (P < 0.001). The immediate drop at time 0 is occurrences of primary nonfunction (i.e., C-peptide never >0.3 ng/mL). Modified from: Barton F et al., Improvement in Outcomes of Clinical Islet Transplantation: 1999–2010 Diabetes Care, 2012. C. NAA/Cho (D) was significantly lower in individuals with T1D on the waiting list (T1DWL) compared with controls, whereas it was near-normal in patients undergoing ITA. D. The Cho-to-Cr ratio was increased in the T1D-WL group compared with both the ITA and CTRL groups, suggesting an increase in degenerative processes (P = 0.01). Modified from D’Addio F et al. Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes. Diabetes Care 2014;37:267–276. 171 172 173 174 175 176 177 178 179 180 181 182 183 184 185 186 187 188 189 190 191 192 193 194 195
endpoints as it is strictly correlated with basal graft function, even when insulin therapy is maintained. In fact, the transplanted islets play a role not only in endogenous insulin secretion but also in glucose counter-regulation. It has been shown that the epinephrine response improves, and endogenous glucose production is restored, with significant normalization of autonomic symptoms contrasting insulin-induced hypoglycemia [25,26]. The overview from the CITR report clearly demonstrates the improved metabolic results in recent times. A significant increase in the rate of insulin independence was seen during the 2007–2010 period: 66% were insulin-independent at one year, 55% at two years, and 44% at three years. From 1999 to 2002, 51% were insulin independent at one year, falling to 36% at two years, and to 27% at three years (P = 0.01). The durability of islet graft function, as measured by fasting C-peptide >0.3 ng/mL, improved significantly during the latter period: the lost of function expressed by the survival curve is almost 10% at four years. These data represent the summary of overall activity. However, single center performance shows interesting results. Some elegant studies underline the value of immunosuppressive and peri-transplant therapy. Bellin et al. provide remarkable data from the Minnesota group on single-donor islet transplantation success in a clinical series of islet transplant recipients, where T-cell depletion induction therapy with ATG was carried out, combined with intensive peri-islet
transplant management, based on the use of tumor necrosis factoralpha inhibition (TNF-␣-I, etanercept). Insulin independence was attained in five of the six recipients at one year; four recipients continued to be insulin-independent at a mean of 3.4 ± 0.8 years post-transplant [27]. A larger study carried out by the same group later confirmed that patients receiving potent induction immunosuppression, with FcR non-binding anti-CD3, or either ATG or alemtuzumab with etanercept, are more than twice as likely to maintain long-term insulin independence for ≥5 years posttransplant compared to those receiving IL-2 receptor antagonists, despite the fact that only a single-donor pancreas was utilized in over 70% of group 1 recipients. Insulin independence rates in these recipients approach those seen in whole-pancreas transplantation [28]. The authors speculated that potent immunosuppressive therapy targets T cells while preserving or expanding regulatory T cells and their function, minimizing cytokine toxicity on transplanted islets. Consequently, the islets can be protected from alloand auto-immune reactions [29–31]. Etanercept might mediate the benefit with two proposed mechanisms: preventing the detrimental effects of cytokine exposure at the time of islet infusion [32]; having a sustained impact on auto-immunity, as shown in animal models at diabetes onset [33]. A prospective trial showed that the addition of exenatide and etanercept to the standard Edmonton protocol (University of Illinois Chicago protocol) is associated with a significantly lower number of islets initially required
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
196 197 198 199 200 201 202 203 204 205 206 207 208 209 210 211 212 213 214 215 216 217 218 219 220
G Model
221 222 223 224 225 226 227 228 229 230 231 232 233 234 235 236 237 238 239 240 241 242 243 244 245 246 247 248 249 250 251 252 253 254 255 256 257 258 259 260 261 262 263 264 265 266 267 268
269
270 271 272 273
274 275 276 277 278 279 280 281 282
YPHRS 2821 1–6
ARTICLE IN PRESS
4
P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
to achieve insulin independence, which was maintained for 15 months [34]. Sixty per cent of these patients were still not carrying out insulin therapy five years later [35]. Exenatide was also used in another study where patients showed chronic islet allograft dysfunction: exogenous insulin was significantly reduced with stable glycemic control [36]. The rationale of exenatide in islet transplantation was based on its metabolic effects: decreased gastric emptying, increased satiety, suppression of glucagon secretion, increased glucose-dependent insulin secretion, and increased peripheral sensitivity to insulin, as previously demonstrated in type-2 diabetes [37]. The hypothesis of its protective effect on islet survival, as demonstrated in preclinical models, has also changed [38]. Recently, the update of the clinical activity performed in Edmonton highlighted the role of some factors that determine success following single-donor islet infusion. Significant factors were: recipient age, insulin requirement at baseline, donor weight, donor BMI, islet transplant mass, and peri-transplant heparin and insulin administration [39]. These results confirm the role of engraftment on long-term transplanted islet survival, and specific strategies during the perioperative period become essential. Primary graft function was seen to be an important parameter of long-term islet transplant outcome. In a study where a consistent mass of islets was transplanted (2 or 3 infusions, mean 12,479 IE/kg) over a period of 90 days, optimal primary graft function (PGF) was associated with prolonged graft survival and better metabolic control: 8 out of 9 patients with optimal PGF maintained insulin independence at two years, compared to 1 out of 5 with suboptimal PGF [40]. The long-term survival of transplanted islets is currently a matter of debate. The Geneva group reported the longest duration of insulin independence: in a case report of islet after kidney transplantation in an insulin-independent patient with excellent metabolic function, who died of cerebral hemorrhage, they demonstrated intrahepatic survival of allogeneic islets of Langerhans for more than 13 years [41]. Insulin immune fluorescence staining demonstrated the absence of insulin-positive cells within the native pancreatic islets, together with the presence of insulinpositive islets in the liver with significant reshaping, discarding the notion that insulin-independence was achieved as a result of native -cell regeneration [42]. Most importantly, ITA was strongly associated with posttransplant rather than pre-transplant behavioral changes and worries linked to hypoglycemia [43]. When rigorous assessment of health-related quality of life (HRQL) is used, ITA patients show better HRQL at one year, although some resume insulin therapy, which indicates the beneficial impact of islet transplantation on glycemic brittleness, independent of poor tolerance to insulin injections [44]. 5.2. Effects on the chronic complications of diabetes The studies focused on the chronic complications of type-1 diabetes in patients who underwent islet transplantation, and how it influenced micro- and macrovascular complications, peripheral neuropathy, and the central nervous system. 5.2.1. Macroangiopathy – cardiovascular complications At our Institute, diabetic complication follow-up of patients receiving islet and kidney transplant was compared with that of type-1 diabetes patients receiving a kidney transplant alone [8]: the islet and kidney group showed improved cardiac function in terms of better diastolic function, QT dispersion, and reduced intima media thickness progression. Patients in the islet-kidney group attained HbA1c values similar to those found to prevent diabetic vascular complications in the Diabetes Control and Complications
Trial [45] and restoration of C-peptide secretion, even if they were not at all insulin independent. Better patient survival, fewer fatal cardiovascular events, and improved endothelial function were observed in a cohort of patients with long-term transplanted islet function plus kidney, compared to patients who had islets that did not function for more than 12 months. This difference did not correlate with glycated hemoglobin levels, but with C-peptide secretion and lower exogenous insulin requirement [46]. 5.2.2. Microangiopathy–retinopathy, nephropathy Color Doppler imaging showed an early increase in retinal arterial and venous blood flow velocities at one year after islet transplantation [47]. More recently, a crossover study [7] demonstrated that there was no progression of diabetic retinopathy and a slower progression of nephropathy after ITA than with intensive medical therapy. Some authors reported that diabetic nephropathy improved after replacement of metabolic control with transplant. First the effects of pancreas alone were clearly demonstrated at biopsies showing the reversion of diabetic nephropathy lesions 10 years after the pancreas transplant [48]. In studies on islet and kidney transplantation, although the pancreatic endocrine function was partially restored, improvement in renal function and kidney graft life span was demonstrated, probably on the base of increased activity in Na/K-ATPase in red blood cells and increased expression of Na/K-ATPase immunoreactivity in tubular cells of the transplanted kidney [49] or on the base of improved NOS expression in the kidney vascular function [50] supported by the partial restoration of C-peptide secretion. Recently, Lehmann et al. demonstrated no difference in the decline of kidney function for more than 10 years comparing patients who received SPK/PAK with SIK/IAK, although glycated hemoglobin was slightly lower and insulin independence rate higher in pancreas than in islet recipients [51]. 5.2.3. Peripheral and central nervous system complications The findings on peripheral neuropathy of the above cited study [7], evaluated by nerve conduction velocity (NCV), did not show significant differences between ITA and patients treated with intensive medical therapy. On the other hand, a longitudinal study based on nerve conduction velocity index, which is not limited by specific intra-individual variability for each nerve trunk, demonstrated an improvement after four and six years in patients receiving an islet and kidney transplant, and not in patients receiving only kidney [9]. Finally, it is important to mention Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy of proton findings on brain metabolism before and after islet transplantation: higher NAA-toCho (N-acetylaspartate to choline, a marker of neuronal density and function) and lower Cho-to-Cr (choline to creatine) ratio values in patients undergoing ITA (Fig. 1C and D), indicating a relative sparing of neuronal function from tissue degeneration and loss. Furthermore, a significant improvement was recorded in mood profile, depression and anxiety, speed of information processing, and attention abilities, with greater maintenance of neuropsychological attitude in islet-transplanted patients compared to those with T1D [10]. 5.3. Complications of islet transplantation A low incidence of complications correlated with the islet transplantation procedure was reported. The percutaneous intrahepatic infusion of islets, with combined ultrasound and fluoroscopic guidance, is considered the safest method. It allows a single puncture attempt in nearly 90% of cases [24], and the significant advantage of an early assessment of
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
283 284 285 286 287 288 289 290 291
292 293 294 295 296 297 298 299 300 301 302 303 304 305 306 307 308 309 310 311 312 313 314 315
316 317 318 319 320 321 322 323 324 325 326 327 328 329 330 331 332 333 334 335 336 337
338
339 340 341 342 343 344
G Model YPHRS 2821 1–6
ARTICLE IN PRESS P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
345 346 347 348 349 350 351 352 353 354 355 356 357 358 359 360 361 362 363 364 365 366 367 368 369 370 371 372 373 374 375 376 377 378
379
380 381 382 383 384 385 386 387 388 389 390
391
bleeding at the end of the procedure. In a larger Edmonton study (278 procedures), 3.7% of cases developed partial portal thrombosis (no cases of complete thrombosis) that resolved within a few weeks with anticoagulation therapy. The packed cell volume >5 mL was highlighted as a risk factor [48,52]. The main concerns in ITA are immunological. Two issues need to be considered: immunosuppressive therapy and allo-autoimmune responses. Severe adverse events of immunosuppression in ITA were not reported. Regarding infection, CMV disease was rarely reported (sieroconversion 6/121; viremia 8/121) [53], and the incidence was lower than in pancreas transplant alone [54]. No post-transplant lymphoproliferative diseases were registered. Occasional solid cancer was described, but not in committed studies. The development of allo- and autoimmune responses after islet transplantation has also to be included in the list of complications. Preformed alloreactive antibodies are an important negative predictor of islet transplant outcome [55]; while preformed pre-transplant autoimmune antibodies only weakly predict post-transplant outcome [56]. In a large study, 46% of recipients underwent important post-transplant donor specific antibodies (DSA) increase; 37% showed an increase or serum conversion of autoantibodies (GADA, IA-2A, ZnT8A), and these findings were almost always associated with a direct decline in islet graft function [53,57]. The possible appearance of allo-antibodies, which could reduce the potential success not only of further islet transplant but also of subsequent solid organ transplant, particularly kidney, have to be considered in the risk/benefit balance. Finally it is important to outline the long-term effects of the immunosuppressive drugs on kidney function. Diabetic nephropathy, clinically diagnosed before the islet transplant, could get worse, while normal function was demonstrated to be well maintained. From this experience the criteria of inclusion for islet transplant alone should be conditioned by renal function [58]. 6. Conclusions Islet transplantation is a well-established treatment for brittle type-1 diabetes, and is specifically indicated when hypoglycemic unawareness is not compatible with daily life. Many clinical trials are under investigation in order to improve the results of long-term graft survival, to expand quality and mass tissue, and to modify the immunological response for tolerance induction. The results are comparable with whole pancreas transplantation in the absence of surgical and infective complications. The final balance of the benefits (no hypoglycemic unawareness, normal glucose control) risks (immunosuppression, sensitization) ratio has always to be taken into account when a patient is recruited for islet transplantation. Acknowledgements
393
The authors wish to thank Michael John for the English language editing of this manuscript.
394
References
392
395 396 397 398 399 400 401 402 403 404 405
[1] The Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long term complications in insulin-dependent diabetes mellitus, N. Engl. J. Med. 353 (1993) 329–986. [2] D.M. Nathan, P.A. Cleary, J.Y. Backlund, S.M. Genuth, J.M. Lachin, T.J. Orchard, et al., Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study Research Group. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes, N. Engl. J. Med. 353 (2005) 2643–2653. [3] P.E. Cryer, Hypoglycemia is the limiting factor in the management of diabetes, Diabetes Metab. Res. Rev. 15 (1999) 42–46.
5
[4] E.R. Seaquist, J. Anderson, B. Childs, P. Cryer, S. Dagogo-Jack, L. Fish, et al., Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society, Diabetes Care 36 (2013) 1384–1395. [5] A.M. Shapiro, J.R. Lakey, E.A. Ryan, G.S. Korbutt, E. Toth, G.L. Warnock, et al., Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen, N. Engl. J. Med. 343 (4) (2000) 230–238. [6] F.B. Barton, M.R. Rickels, R. Alejandro, B.J. Hering, S. Wease, B. Naziruddin, et al., Improvement in outcomes of clinical islet transplantation: 1999–2010, Diabetes Care 35 (2012) 1436–1445. [7] D.M. Thompson, M. Meloche, Z. Ao, B. Paty, P. Keown, R.J. Shapiro, et al., Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy, Transplantation 91 (3) (2011) 373–378. [8] P. Fiorina, C. Gremizzi, P. Maffi, R. Caldara, D. Tavano, L. Monti, et al., Islet transplantation is associated with an improvement of cardiovascular function in type 1 diabetic kidney transplant patients, Diabetes Care 28 (2005) 1358–1365. [9] U. Del Carro, P. Fiorina, S. Amadio, L. De Toni Franceschini, A. Petrelli, S. Menini, et al., Evaluation of polineuropathy markers in type 1 diabetic kidneytransplant patients and effects of islet transplantation: neurophysiological and skin biopsy longitudinal analysis, Diabetes Care 30 (12) (2007) 3063–3069. [10] F. D’Addio, P. Maffi, P. Vezzulli, A. Vergani, A. Mello, R. Bassi, et al., Islet transplantation stabilizes hemostatic abnormalities and cerebral metabolism in individuals with type 1 diabetes, Diabetes Care 37 (2014) 267–276. [11] C. Ricordi, P.E. Lacy, E.H. Finke, B.J. Olack, D.W. Scharp, Automated method for isolation of human pancreatic islets, Diabetes 37 (4) (1988) 413–420. [12] R. Nano, B. Clissi, R. Melzi, G. Calori, P. Maffi, B. Antonioli, et al., Islet isolation for allotransplantation: variables associated with successful islet yield and graft function, Diabetologia 48 (2005) 906–912. [13] G.M. Ponte, A. Pileggi, S. Messinger, A. Alejandro, H. Ichii, D.A. Baidal, et al., Toward maximizing the success rates of human islet isolation: Influence of donor and isolation factors, Cell Transplant. 16 (2007) 595–607. [14] N. Niclauss, D. Bosco, P. Morel, S. Demuylder-Mischler, C. Brault, L. MilliatGuittard, et al., Influence of donor age on islet isolation and transplantation outcome, Transplantation 91 (2011) 360–366. [15] D.E. Hilling, E. Bouwman, O.T. Terpstra, P.J. Marang-van de Mheen, Effects of donor-, pancreas-, and isolation-related variables on human islet isolation outcome: a systematic review, Cell Transplant. 23 (2014) 921–928. [16] A.N. Balamurugan, B. Naziruddin, A. Lockridge, M. Tiwari, G. Loganathan, M. Takita, et al., Islet product characteristics and factors related to successful human islet transplantation from the Collaborative Islet Transplant Registry (CITR), 1999–2010, Am. J. Transplant. 14 (2014) 2595–2606. [17] J. Movassat, C. Saulnier, B. Portha, Insulin administration enhances growth of the beta-cell mass in streptozotocin-treated newborn rats, Diabetes 46 (1997) 1445–1452. [18] T. Kitamura, J. Nakae, Y. Kitamura, Y. Kido, W.H. Biggs III, C.V. Wright, et al., The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth, J. Clin. Investig. 110 (2002) 1839–1847. [19] F. Bertuzzi, C. Ricordi, Beta-cell replacement in immunosuppressed recipients: old and new clinical indications, Acta Diabetol. 44 (2007) 171–176, http://dx. doi.org/10.1007/s00592-007-0020-20-20-20 [20] American Diabetes Association, Pancreas and islet transplantation in type 1 diabetes, Diabetes Care 29 (4) (2006) 935. [21] The DCCT Research Group, Hypoglycemia in the Diabetes Control and Complications Trial, Diabetes 46 (1997) 271–286. [22] R.G. McCoy, H.K. Van Houten, J.Y. Ziegenfuss, N.D. Shah, R.A. Wermers, S.A. Smith, Increased mortality of patients with diabetes reporting severe hypoglycemia, Diabetes Care 35 (2012) 1897–1901. [23] M. Venturini, E. Angeli, P. Maffi, P. Fiorina, F. Bertuzzi, M.V. Salvioni, et al., Technique complications and therapeutic efficacy of percutaneous transplantation of human pancreatic islet cells in type 1 diabetes: the role of US, Radiology 234 (2) (2005) 617–624. [24] P. Maffi, G. Balzano, M. Ponzoni, R. Nano, V. Sordi, R. Melzi, A. Mercalli, M. Scavini, A. Esposito, et al., Autologous pancreatic islet transplantation in human bone marrow, Diabetes 62 (2013) 3523–3531. [25] M.R. Rickels, C. Fuller, C. Dalton-Bakes, E. Markmann, M. Palanjian, K. Cullison, et al., Restoration of glucose counterregulation by islet transplantation in longstanding type 1 diabetes, Diabetes (2014) 141620. [26] M. Ang, C. Meyer, M.D. Brendel, R.G. Bretzel, T. Linn, Magnitude and mechanisms of glucose counterregulation following islet transplantation in patients with type 1 diabetes suffering from severe hypoglycaemic episodes, Diabetologia 57 (2014) 623–632. [27] M.D. Bellin, R. Kandaswamy, J. Parkey, H.J. Zhang, B. Liu, S.H. Ihm, et al., Prolonged insulin independence after islet allotransplants in recipients with type 1 diabetes, Am. J. Transplant. 8 (11) (2008) 2463–2470. [28] M.D. Bellin, F.B. Barton, A. Heitman, J.V. Harmon, R. Kandaswamy, A.N. Balamurugan, et al., Potent induction immunotherapy promotes long-term insulin independence after islet transplantation in type 1 diabetes, Am. J. Transplant. 12 (6) (2012) 1576–1583. [29] P. Monti, M. Scirpoli, P. Maffi, N. Ghidoli, F. De Taddeo, F. Bertuzzi, et al., Islet transplantation in patients with autoimmune diabetes induces homeostatic cytokines that expand autoreactive memory T cells, J. Clin. Invest. 118 (2008) 1806–1814. [30] B. Keymeulen, E. Vandemeulebroucke, A.G. Ziegler, C. Mathieu, L. Kaufman, G. Hale, et al., Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes, N. Engl. J. Med. 352 (2005) 2598–2608.
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
406 407 408 409 410 411 412 413 414 415 416 417 418 419 420 421 422 423 424 425 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 452 453 454 455 456 457 458 459 460 461 462 463 464 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 486 487 488 489 490 491
G Model
492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 509 510 511 512 513 514 515 516 517 518 519 520 521 522 523 524 525 526 527 528 529 530 531 532 533 534 535 536 537 538 539
YPHRS 2821 1–6
ARTICLE IN PRESS
6
P. Maffi, A. Secchi / Pharmacological Research xxx (2015) xxx–xxx
[31] K.C. Herold, S. Gitelman, C. Greenbaum, J. Puck, W. Hagopian, P. Gottlieb, et al., Treatment of patients with new onset type 1 diabetes with a single course of anti-CD3 mAb Teplizumab preserves insulin production for up to 5 years, Clin. Immunol. 132 (2009) 166–173. [32] A. Rabinovitch, W. Sumoski, R.V. Rajotte, G.L. Warnock, Cytotoxic effects of cytokines on human pancreatic islet cells in monolayer culture, J. Clin. Endocrinol. Metab. 71 (1990) 152–156. [33] X.D. Yang, R. Tisch, S.M. Singer, Z.A. Cao, R.S. Liblau, R.D. Schreiber, et al., Effect of tumor necrosis factor alpha on insulin-dependent diabetes mellitus in NOD mice: I. The early development of autoimmunity and the diabetogenic process, J. Exp. Med. 180 (1994) 995–1004. [34] A. Gangemi, P. Salehi, B. Hatipoglu, J. Martellotto, Barbaro, J.B. Kuechle, et al., Islet transplantation for brittle type 1 diabetes: the UIC protocol, Am. J. Transplant. 8 (2008) 1250–1261. [35] M. Qi, K. Kinzer, K.K. Danielson, J. Martellotto, B. Barbaro, Y. Wang, et al., Fiveyear follow-up of patients with type 1 diabetes transplanted with allogeneic islets: the UIC experience, Acta Diabetol. 51 (5) (2014) 833–843. [36] T. Froud, R.N. Faradji, A. Pileggi, S. Messinger, D.A. Baidal, G.M. Ponte, et al., The use of exenatide in islet transplant recipients with chronic allograft dysfunction: safety, efficacy and metabolic effects, Transplantation 86 (1) (2008) 36–45. [37] R.A. DeFronzo, R.E. Ratner, J. Han, D.D. Kim, M.S. Fineman, A.D. Baron, Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes, Diabetes Care 28 (5) (2005) 1092–1100. [38] Y. Li, T. Hansotia, B. Yusta, F. Ris, P.A. Halban, D.J. Drucker, Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis, J. Biol. Chem. 278 (1) (2003) 471–478. [39] D.P. Al-Adra, R.S. Gill, S. Imes, D. O’Gorman, T. Kin, S.J. Axford, et al., Single-donor islet transplantation and long-term insulin independence in select patients with type 1 diabetes mellitus, Transplantation 98 (9) (2014) 1007–1012. [40] M.C. Vantyghem, J. Kerr-Conte, L. Arnalsteen, G. Sergent, F. Defrance, V. Gmyr, et al., Primary graft function, metabolic control and graft survival after islet transplantation, Diabetes Care 32 (2009) 1473–1478. [41] Y.D. Muller, S. Gupta, P. Morel, S. Borot, F. Bettens, M.E. Truchetet, et al., Transplanted human pancreatic islets after long-term insulin independence, Am. J. Transplant. 13 (2013) 1093–1097. [42] H.A. Keenan, J.K. Sun, J. Levine, A. Doria, L.P. Aiello, G. Eisenbarth, et al., Residual insulin production and pancreatic -cell turnover after 50 years of diabetes: Joslin Medalist Study, Diabetes 59 (2010) 2846–2853. [43] D.M. Radosevich, R. Jevne, M. Bellin, R. Kandaswamy, D.E.R. Sutherland, B.J. Hering, Comprehensive health assessment and five-yr follow-up of allogeneic islet transplant recipients, Clin. Transplant. 27 (2013) E715–E724. [44] P.Y. Benhamou, L. Milliat-Guittard, A. Wojtusciszyn, L. Kessler, C. Toso, R. Baertschiger, et al., on behalf of the GRAGIL group. Quality of life after islet transplantation: data from the GRAGIL 1 and 2 trials, Diabet. Med. 26 (2009) 617–621. [45] Diabetes Control and Complications Trial Research Group, The effect of intensive treatment of diabetes on the development and progression of long term
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53]
[54]
[55]
[56]
[57]
[58]
complications in insulin-dependent mellitus, N. Engl. J. Med. 329 (1993) 977–986. P. Fiorina, F. Folli, F. Bertuzzi, P. Maffi, G. Finzi, M. Venturini, et al., Long-term beneficial effect of islet transplantation on diabetic macro-/microangiopathy in type 1 diabetic kidney-transplanted patients, Diabetes Care 26 (2003) 1129–1136. M. Venturini, P. Fiorina, P. Maffi, C. Losio, A. Vergani, A. Secchi, et al., Early increase of retinal arterial and venous blood flow velocities at color Doppler imaging in brittle type 1 diabetes after islet transplant alone, Transplantation 81 (2006) 1274–1277. P. Fioretto, M.W. Steffes, D.E. Sutherland, F.C. Goetz, M. Mauer, Reversal of lesions of diabetic nephropathy after pancreas transplantation, N. Engl. J. Med. 339 (2) (1998) 69–75. P. Fiorina, F. Folli, P. Zerbini, P. Maffi, C. Gremizzi, V. Di Carlo, et al., Islet transplantation is associated with improvement of renal function among uremic patients with type 1 diabetes mellitus and kidney transplants, J. Am. Soc. Nephrol. 14 (8) (2003) 2150–2158. P. Fiorina, M. Venturini, F. Folli, C. Losio, P. Maffi, C. Placidi, et al., Natural history of kidney graft survival, hypertrophy, and vascular function in end stage renal disease type 1 diabetic kidney transplanted patients: beneficial impact of pancreas and successful islet cotransplantation, Diabetes Care 28 (6) (2005) 1303–1310. R. Lehmann, J. Graziano, J. Brockmann, T. Pfammatter, P. Kron, O. de Rougemont, et al., Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation in type 1 diabetes: a prospective 13-year follow-up, Diabetes Q3 Care (2015). T. Kawahara, T. Kin, S. Kashkoush, B. Gala-Lopez, D.L. Bigam, N.M. Kneteman, et al., Portal vein thrombosis is a potentially preventable complication in clinical islet transplantation, Am. J. Transplant. 11 (2011) 2700–2707. B.L. Gala-Lopez, P.A. Senior, A. Koh, S.M. Kashkoush, T. Kawahara, T. Kin, A. Humar, A.M. Shapiro, Late cytomegalovirus transmission and impact of T-depletion in clinical islet transplantation, Am. J. Transplant. 11 (2011) 2708–2714. P. Maffi, M. Scavini, C. Socci, L. Piemonti, R. Caldara, C. Gremizzi, et al., Risks and benefits of transplantation in the cure of type 1 diabetes: whole pancreas versus islet, Rev. Diabet. Stud. 8 (1) (2011) 44–50. P.M. Campbell, A. Salam, E.A. Ryan, P. Senior, B.W. Paty, D. Bigam, et al., Pretransplant HLA antibodies are associated with reduced graft survival after clinical islet transplantation, Am. J. Transplant. 7 (2007) 1242–1248. E. Bosi, S. Braghi, P. Maffi, M. Scirpoli, F. Bertuzzi, G. Pozza, et al., Autoantibody response to islet transplantation in type 1 diabetes, Diabetes 50 (2001) 2464–2471. L. Piemonti, M.J. Everly, P. Maffi, M. Scavini, F. Poli, R. Nano, et al., Alloantibody and autoantibody monitoring predicts islet transplantation outcome in human type 1 diabetes, Diabetes 62 (5) (2013) 1656–1664. P. Maffi, F. Bertuzzi, F. De Taddeo, P. Magistretti, R. Nano, P. Fiorina, et al., Kidney function after islet transplant alone in type 1 diabetes: impact of immunosuppressive therapy on progression of diabetic nephropathy, Diabetes Care 30 (5) (2007) 1150–1155.
Please cite this article in press as: P. Maffi, A. Secchi, Clinical results of islet transplantation, Pharmacol Res (2015), http://dx.doi.org/10.1016/j.phrs.2015.04.010
540 541 542 543 544 545 546 547 548 549 550 551 552 553 554 555 556 557 558 559 560 561 562 563 564 565 566 567 568 569 570 571 572 573 574 575 576 577 578 579 580 581 582 583 584 585 586 587 588
