Outcomes of Clinical Islet Transplantation: 1999-2010
Outcomes of Clinical Islet Transplantation: 1999-2010
This analysis was based on 677 recipients of allogeneic islet transplantation who consented to the reporting of their data to the CITR, with 214 recipients in 1999–2002 (early), 255 in mid-2003–2006, and 208 in 2007–2010 (recent); 423 (62%) came from North America, and 254 (38%) were reported from the European and Australian JDRF sites. Transplants comprised islet alone in 575 (85%) and IAK or simultaneous islet kidney (IAK/SIK) transplant in 102 (15%). The CIT enrolled 46 (7%) in 2008–2010. They received 1,375 islet infusions from 1,502 donors, of which ~10% were islets from 2 to 3 donors infused on the same day, considered here as "multiple donor infusion." Approximately 36% of the recipients received only one infusion, 44% received two, 18% received three, 1.3% received four, and one person received six infusions.
The CITR data represent 81% of all islet transplants performed in the North American and JDRF European and Australian centers between 1999 and 2010. The number of new islet allograft recipients doubled yearly between 1999 and 2002 (Fig. 1). A marked decline in activity from 2002 to 2003 reflected a saturation of then-existing protocol enrollments, combined with tempered enthusiasm for the procedure after some centers reported waning insulin independence at 2–3 years. The number of North American centers performing islet transplants continued to rise through 2005, although the annual number of islet allografts remained less than the 2002 levels. In 2007, there were fewer than half as many North American centers performing islet transplants and one-third of the total number of islet allografts performed compared with 2005 at a time when the commonly used collagenase enzyme Liberase became unavailable. A distinct resurgence in islet transplant activity occurred in 2008 with the available collagenase products and the start-up of the CIT trials.
(Enlarge Image)
Figure 1.
Islet allograft recipients (N = 677) registered in CITR according to type of transplant (n per year; top), induction immunosuppression at first infusion (% by year; center), and maintenance immunosuppression at first infusion (% by year; bottom). ITA, islet transplant alone.
Figure 1 also shows substantial shifts in immunosuppression strategies implemented during the 12-year period. The early and mideras were dominated by the Edmonton Protocol, which used an interleukin 2 receptor antagonist (e.g., daclizumab) for induction and a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus), together with a calcineurin inhibitor (CNI, e.g., tacrolimus) for maintenance immunosuppression. In the most recent era, there has been a shift to induction with a T-cell depleting (TCD) antibody, with or without an inhibitor of tumor necrosis factor-α (TNF-α; e.g., etanercept) and maintenance with an mTOR inhibitor or an inosine monophosphate dehydrogenase inhibitor (e.g., mycophenolic acid) combined with a CNI.
Table 1 summarizes the preinfusion recipient characteristics according to era. Over time, recipients with C-peptide ≥0.3 ng/mL have been excluded. Increasingly, recipients have been selected at older age and with longer type 1 diabetes duration, requiring slightly less insulin and having better kidney function, as indicated by lower serum creatinine, suggesting more appropriate patient selection. Consistent with trends in clinical practice, more were using insulin pumps for insulin delivery, which may explain the slightly lower daily insulin requirement, and more were taking lipid-lowering medications. Following national trends, donor weight increased, and consistent with trends in critical care medicine, more donors received insulin with a consequent decrease in donor glucose. Donor HbA1c, when sampled, remained within normal levels in all eras. There were also definite shifts in preservation method and collagenase type, and more islet preparations were cultured. The clinical effects of procurement, processing, and final islet characteristics are the focus of a separate analysis. Recent years have seen a substantial decline in the use of daclizumab, with a substantial rise in polyclonal T-cell–depleting antibodies and/or etanercept, as well as notable declines in sirolimus use, with increased use of mycophenolic acid.
There were increasing levels of missing data with longer follow-up, which is a mixture of data unavailable from the medical record and data still pending entry into the registry. The percentages of missing data for insulin independence were 3% at 1 year, 5% at 3 years, and 7% at 5 years and for other primary end points were 10 to 20% over years 1–3.
Of those who received transplants in the 1999–2002 era, 51% were insulin-independent at 1-year after the first infusion, regardless of reinfusion, and this declined to 36% at 2 years and to 27% at 3 years. By contrast in the 2007–2010 era, 66% were insulin-independent at 1 year, 55% at 2 years, and 44% at 3 years (P = 0.01, Fig. 2A). The decline in the rate of insulin independence during 5 years of follow-up in all eras is significant (P < 0.001). The difference in this decline among the three eras (P = 0.006 for years-by-era) indicates that the rate of decline is less steep, showing notable improvement in durability in the most recent era. Durability of islet graft function, as measured by fasting C-peptide ≥0.3 ng/mL, improved significantly over the eras (P < 0.001, Fig. 2B, left). The rate of graft function loss was significantly reduced if insulin independence was previously achieved, an effect seen in all eras (Fig. 2B, right). Nearly all islet recipients had significant improvements in HbA1c and fasting blood glucose after islet transplantation. The composite end point of HbA1c <6.5% or a drop by two or more percentage points shows improvement from the early era to the mid era (P = 0.03), although no further improvement in the most recent era, with 2–5-year success rates of 50–60% in the recent era (Fig. 2C, left). Fasting blood glucose showed a marked improvement from the early to mid eras (P < 0.01, not shown).
(Enlarge Image)
Figure 2.
A: Rates of insulin independence after allogeneic islet infusion (islet transplant alone and IAK), annually after last infusion. Left: By era (P = 0.02). Right: By induction immunosuppression category (P < 0.01). B: Durability of graft function (basal C-peptide ≥0.3 ng/mL) after the last infusion, by era (P < 0.001; left). The immediate drop at time 0 is occurrences of primary nonfunction (i.e., C-peptide never ≥0.3 ng/mL). In the most recent era, 95% of those who ever achieved insulin independence (II) retained graft function through 3 years after last infusion compared with 70% for those who never achieved II (P < 0.001; right). C: Percentage of patients with HbA1c <6.5% or drop by two percentage points (P = 0.03; left); and absence of severe hypoglycemic events regardless of complete graft failure (P = NS by era; there were insufficient data from 2007–2010; right). D: The percentage with HbA1c <6.5% or drop by 2% increases with increasing C-peptide level (P < 0.001; left), as does absence of severe hypoglycemic events (P < 0.001; right), annually after the last infusion. (A high-quality color representation of this figure is available in the online issue.)
Severe hypoglycemia was prevalent at first infusion in >90% of all subjects in all eras. Available data on severe hypoglycemic events, regardless of previous graft loss (C-peptide <0.3 ng/mL without recovery), shows >90% remained free of severe hypoglycemic events in all eras, and this relationship persisted through 5 years of follow-up (Fig. 2C, right). Any differences by era on resolution of severe hypoglycemic events were neither detectable nor important relative to this sustained, high level of benefit. If data on severe hypoglycemic events were missing and previous complete graft loss was counted as return to severe hypoglycemic events—an extreme assumption—there was still improvement in 2003–2006 compared with 1999–2002 at years 2–4 (P = 0.03, not shown).
Concurrent C-peptide is a strong correlate of all the other primary outcomes: the higher the C-peptide, the greater the likelihood of HbA1c <6.5% or a drop by two percentage points (P < 0.001; Fig. 2D), the greater the likelihood of absence of severe hypoglycemic events (P < 0.001; Fig. 2D), the greater the likelihood of fasting blood glucose in the 60–140 mg/dL range (P < 0.001, not shown), and the greater the likelihood of insulin independence (P < 0.001, not shown).
A comprehensive model of all predictive factors—noting the shifts in patient age and immunosuppression strategies over the eras (Table 1)—largely accounted for the differences by era in insulin independence (Table 2). The effect of T-cell–depleting agents in conjunction with TNF-α inhibitors shows on enduring insulin independence is confirmed: 50–62% of recipients receiving this induction regimen were insulin-independent at years 3–5 after the last infusion (Fig. 2A, right), compared with 34–43% for those not receiving TCD+TNF-α inhibitors.
Reinfusion is performed when the first graft loses function completely or declining function is proven by declining C-peptide levels. Islet reinfusion has decreased substantially during the 12-year period: 48% of recipients were reinfused by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01).
Mortality is low in this group of type 1 diabetic individuals with substantial disease burden, with stable event rates during the 12-year period (Fig. 3A). The incidence of life-threatening events has declined (P = 0.002; Fig. 3B). The incidence of any CRAE in year 1 declined from 50 to 53% in 1999–2006 and to 38% in 2007–2010 (P = 0.02; Fig. 3C). Peritoneal hemorrhage or gallbladder perforation declined from 5.4% in 1999–2003 to 3.1% in 2007–2010. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculated glomerular filtration rate (GFR) declined after islet transplantation (Fig. 3D); however, there are no published comparable follow-up data in similar groups of type 1 diabetes. No primary efficacy or safety end points were associated with recipient or donor sex or ethnicity.
(Enlarge Image)
Figure 3.
A: Mortality by era (P = 0.49). B: Life-threatening events by era (P = 0.01). C: Incidence of any adverse event (AE) in year 1 of first infusion (P = 0.02 by era). D: CKD-EPI calculated glomerular filtration rate, by era.
Results
This analysis was based on 677 recipients of allogeneic islet transplantation who consented to the reporting of their data to the CITR, with 214 recipients in 1999–2002 (early), 255 in mid-2003–2006, and 208 in 2007–2010 (recent); 423 (62%) came from North America, and 254 (38%) were reported from the European and Australian JDRF sites. Transplants comprised islet alone in 575 (85%) and IAK or simultaneous islet kidney (IAK/SIK) transplant in 102 (15%). The CIT enrolled 46 (7%) in 2008–2010. They received 1,375 islet infusions from 1,502 donors, of which ~10% were islets from 2 to 3 donors infused on the same day, considered here as "multiple donor infusion." Approximately 36% of the recipients received only one infusion, 44% received two, 18% received three, 1.3% received four, and one person received six infusions.
The CITR data represent 81% of all islet transplants performed in the North American and JDRF European and Australian centers between 1999 and 2010. The number of new islet allograft recipients doubled yearly between 1999 and 2002 (Fig. 1). A marked decline in activity from 2002 to 2003 reflected a saturation of then-existing protocol enrollments, combined with tempered enthusiasm for the procedure after some centers reported waning insulin independence at 2–3 years. The number of North American centers performing islet transplants continued to rise through 2005, although the annual number of islet allografts remained less than the 2002 levels. In 2007, there were fewer than half as many North American centers performing islet transplants and one-third of the total number of islet allografts performed compared with 2005 at a time when the commonly used collagenase enzyme Liberase became unavailable. A distinct resurgence in islet transplant activity occurred in 2008 with the available collagenase products and the start-up of the CIT trials.
(Enlarge Image)
Figure 1.
Islet allograft recipients (N = 677) registered in CITR according to type of transplant (n per year; top), induction immunosuppression at first infusion (% by year; center), and maintenance immunosuppression at first infusion (% by year; bottom). ITA, islet transplant alone.
Figure 1 also shows substantial shifts in immunosuppression strategies implemented during the 12-year period. The early and mideras were dominated by the Edmonton Protocol, which used an interleukin 2 receptor antagonist (e.g., daclizumab) for induction and a mammalian target of rapamycin (mTOR) inhibitor (e.g., sirolimus), together with a calcineurin inhibitor (CNI, e.g., tacrolimus) for maintenance immunosuppression. In the most recent era, there has been a shift to induction with a T-cell depleting (TCD) antibody, with or without an inhibitor of tumor necrosis factor-α (TNF-α; e.g., etanercept) and maintenance with an mTOR inhibitor or an inosine monophosphate dehydrogenase inhibitor (e.g., mycophenolic acid) combined with a CNI.
Table 1 summarizes the preinfusion recipient characteristics according to era. Over time, recipients with C-peptide ≥0.3 ng/mL have been excluded. Increasingly, recipients have been selected at older age and with longer type 1 diabetes duration, requiring slightly less insulin and having better kidney function, as indicated by lower serum creatinine, suggesting more appropriate patient selection. Consistent with trends in clinical practice, more were using insulin pumps for insulin delivery, which may explain the slightly lower daily insulin requirement, and more were taking lipid-lowering medications. Following national trends, donor weight increased, and consistent with trends in critical care medicine, more donors received insulin with a consequent decrease in donor glucose. Donor HbA1c, when sampled, remained within normal levels in all eras. There were also definite shifts in preservation method and collagenase type, and more islet preparations were cultured. The clinical effects of procurement, processing, and final islet characteristics are the focus of a separate analysis. Recent years have seen a substantial decline in the use of daclizumab, with a substantial rise in polyclonal T-cell–depleting antibodies and/or etanercept, as well as notable declines in sirolimus use, with increased use of mycophenolic acid.
There were increasing levels of missing data with longer follow-up, which is a mixture of data unavailable from the medical record and data still pending entry into the registry. The percentages of missing data for insulin independence were 3% at 1 year, 5% at 3 years, and 7% at 5 years and for other primary end points were 10 to 20% over years 1–3.
Of those who received transplants in the 1999–2002 era, 51% were insulin-independent at 1-year after the first infusion, regardless of reinfusion, and this declined to 36% at 2 years and to 27% at 3 years. By contrast in the 2007–2010 era, 66% were insulin-independent at 1 year, 55% at 2 years, and 44% at 3 years (P = 0.01, Fig. 2A). The decline in the rate of insulin independence during 5 years of follow-up in all eras is significant (P < 0.001). The difference in this decline among the three eras (P = 0.006 for years-by-era) indicates that the rate of decline is less steep, showing notable improvement in durability in the most recent era. Durability of islet graft function, as measured by fasting C-peptide ≥0.3 ng/mL, improved significantly over the eras (P < 0.001, Fig. 2B, left). The rate of graft function loss was significantly reduced if insulin independence was previously achieved, an effect seen in all eras (Fig. 2B, right). Nearly all islet recipients had significant improvements in HbA1c and fasting blood glucose after islet transplantation. The composite end point of HbA1c <6.5% or a drop by two or more percentage points shows improvement from the early era to the mid era (P = 0.03), although no further improvement in the most recent era, with 2–5-year success rates of 50–60% in the recent era (Fig. 2C, left). Fasting blood glucose showed a marked improvement from the early to mid eras (P < 0.01, not shown).
(Enlarge Image)
Figure 2.
A: Rates of insulin independence after allogeneic islet infusion (islet transplant alone and IAK), annually after last infusion. Left: By era (P = 0.02). Right: By induction immunosuppression category (P < 0.01). B: Durability of graft function (basal C-peptide ≥0.3 ng/mL) after the last infusion, by era (P < 0.001; left). The immediate drop at time 0 is occurrences of primary nonfunction (i.e., C-peptide never ≥0.3 ng/mL). In the most recent era, 95% of those who ever achieved insulin independence (II) retained graft function through 3 years after last infusion compared with 70% for those who never achieved II (P < 0.001; right). C: Percentage of patients with HbA1c <6.5% or drop by two percentage points (P = 0.03; left); and absence of severe hypoglycemic events regardless of complete graft failure (P = NS by era; there were insufficient data from 2007–2010; right). D: The percentage with HbA1c <6.5% or drop by 2% increases with increasing C-peptide level (P < 0.001; left), as does absence of severe hypoglycemic events (P < 0.001; right), annually after the last infusion. (A high-quality color representation of this figure is available in the online issue.)
Severe hypoglycemia was prevalent at first infusion in >90% of all subjects in all eras. Available data on severe hypoglycemic events, regardless of previous graft loss (C-peptide <0.3 ng/mL without recovery), shows >90% remained free of severe hypoglycemic events in all eras, and this relationship persisted through 5 years of follow-up (Fig. 2C, right). Any differences by era on resolution of severe hypoglycemic events were neither detectable nor important relative to this sustained, high level of benefit. If data on severe hypoglycemic events were missing and previous complete graft loss was counted as return to severe hypoglycemic events—an extreme assumption—there was still improvement in 2003–2006 compared with 1999–2002 at years 2–4 (P = 0.03, not shown).
Concurrent C-peptide is a strong correlate of all the other primary outcomes: the higher the C-peptide, the greater the likelihood of HbA1c <6.5% or a drop by two percentage points (P < 0.001; Fig. 2D), the greater the likelihood of absence of severe hypoglycemic events (P < 0.001; Fig. 2D), the greater the likelihood of fasting blood glucose in the 60–140 mg/dL range (P < 0.001, not shown), and the greater the likelihood of insulin independence (P < 0.001, not shown).
A comprehensive model of all predictive factors—noting the shifts in patient age and immunosuppression strategies over the eras (Table 1)—largely accounted for the differences by era in insulin independence (Table 2). The effect of T-cell–depleting agents in conjunction with TNF-α inhibitors shows on enduring insulin independence is confirmed: 50–62% of recipients receiving this induction regimen were insulin-independent at years 3–5 after the last infusion (Fig. 2A, right), compared with 34–43% for those not receiving TCD+TNF-α inhibitors.
Reinfusion is performed when the first graft loses function completely or declining function is proven by declining C-peptide levels. Islet reinfusion has decreased substantially during the 12-year period: 48% of recipients were reinfused by 1 year in 2007–2010 vs. 60–65% in 1999–2006 (P < 0.01).
Mortality is low in this group of type 1 diabetic individuals with substantial disease burden, with stable event rates during the 12-year period (Fig. 3A). The incidence of life-threatening events has declined (P = 0.002; Fig. 3B). The incidence of any CRAE in year 1 declined from 50 to 53% in 1999–2006 and to 38% in 2007–2010 (P = 0.02; Fig. 3C). Peritoneal hemorrhage or gallbladder perforation declined from 5.4% in 1999–2003 to 3.1% in 2007–2010. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) calculated glomerular filtration rate (GFR) declined after islet transplantation (Fig. 3D); however, there are no published comparable follow-up data in similar groups of type 1 diabetes. No primary efficacy or safety end points were associated with recipient or donor sex or ethnicity.
(Enlarge Image)
Figure 3.
A: Mortality by era (P = 0.49). B: Life-threatening events by era (P = 0.01). C: Incidence of any adverse event (AE) in year 1 of first infusion (P = 0.02 by era). D: CKD-EPI calculated glomerular filtration rate, by era.
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