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. Author manuscript; available in PMC: 2020 Nov 11.
Published in final edited form as: Transplantation. 2008 Dec 27;86(12):1799–1802. doi: 10.1097/TP.0b013e31819143ec

Islet Autotransplant Outcomes After Total Pancreatectomy: A Contrast to Islet Allograft Outcomes

David E R Sutherland 1,5, Angelika C Gruessner 2, Annelisa M Carlson 1, Juan J Blondet 3, A N Balamurugan 1, Katie F Reigstad 1, Gregory J Beilman 3, Melena D Bellin 4, Bernhard J Hering 1
PMCID: PMC7656854  NIHMSID: NIHMS1642895  PMID: 19104425

Abstract

Introduction.

Islet allografts are currently associated with a high rate of early insulin independence, but after 1 year insulin-independence rates rapidly decline for unclear reasons. In contrast, as shown here, islet autotransplants (IATs) show durable function and extended insulin-independence rates, despite a lower beta-cell mass.

Methods.

IAT function was determined in 173 patients after total pancreatectomy at our center. Islet function was considered full in insulin-independent patients, partial when euglycemic on once-daily long-acting insulin (all tested were C-peptide positive), and failed if on a standard diabetic regimen. Outcomes for autoislet recipients by Kaplan-Meier survival analysis were compared with those of alloislet recipients in the Collaborative Islet Transplant Registry.

Results.

IAT function (full/partial combined) and insulin independence correlated with islet yield. Overall only 65% functioned within the first year, and only 32% were insulin independent, but of IATs that functioned initially (n=112), 85% remained so 2-years later, in contrast to 66% of allografts (n=262). Of IAT recipients who became insulin independent (n=55),74% remained so 2-years later versus 45% of initially insulin-independent allograft recipients (n=154). Of IATs that functioned or induced insulin independence, the rates at 5 years were 69% and 47%, respectively.

Conclusion.

Islet function is more resilient in autografts than allografts. Indeed, the 5-year insulin-independence persistence rate for IATs is similar to the 2-year rate for allografts. Several factors unique to allocases are likely responsible for the differences, including donor brain death, longer cold ischemia time, diabetogenic immunosuppression, and auto- and alloimmunity. IAT outcomes provide a minimum theoretical standard to work toward in allotransplantation.

Keywords: Islet, Insulin, Pancreatectomy, Pancreatitis, Surgery

Islet allografts with a large beta-cell mass (>10,000 islet equivalents [IE]/kg) are currently associated with a high rate of islet function (as measured by C-peptide levels) and early insulin independence in recipients with type 1 diabetes mellitus; however, after 1 year posttransplant, insulin-independence rates rapidly decline for reasons that are not clear (immunologic or nonimmunologic?) (1-3). At the University of Minnesota we have a large experience, extending back to 1977 (4), with intraportal islet autotransplants (IATs) performed to preserve as much beta-cell mass and insulin-secretory capacity as possible at the time of total pancreatectomy (TP) to treat painful chronic pancreatitis (5-9).

As presented here, islet autografts show durable function and are associated with a high rate of persistence of insulin independence, once established, even though the beta-cell mass, as estimated by the IE transplanted (10), is less than for islet allografts. Islet allografts are affected by various circumstances, including metabolic perturbations in the donor from brain death (11), relatively long cold ischemia times before islet isolation from the donor pancreas (12), recipient alloimmune responses to the donor tissue, recipient autoimmunity specifically against beta cells (13,14), and the diabetogenic effect of the immunosuppressive drugs given to prevent rejection (15). In contrast, IATs are performed in the absence of such compounding factors; thus, analysis of islet autograft outcomes can help us interpret islet allograft outcomes, and provide a minimum standard for long-term success as corresponding factors are overcome.

Herein, we present the results of an analysis of islet function over time in our pancreatectomized autograft recipients, when compared with the outcomes for type 1 diabetic islet allograft recipients as reported by the Collaborative Islet Transplant Registry (CITR) (1).

MATERIALS AND METHODS

IAT Patient Population

From February 1977 through December 2007, at the University of Minnesota, 193 adult patients with chronic pancreatitis underwent TP (n=126) or near (95%) total (n=18) or completion (resulting in a total) pancreatectomy (n=35), or partial pancreatectomy (n=14), along with an intraportal IAT. The cases of partial pancreatectomy were excluded from the analyses of islet graft function but the near total were included with the total and completion pancreatectomy group (TP) because the technique we used left, at most, only tiny pancreas fragments on the retained duodenum, and in others in whom we had performed a near TP without IAT, all became fully diabetic. In addition, graft function and insulin-independence rates did not differ between those undergoing total, near total, or completion pancreatectomy (see Results section).

Islet Isolation and Transplantation

The basic technique of autoislet preparation from 1977 to 2007 was the same: dispersion of the pancreas by collagenase digestion at 37°C, initiated by intraductal injection in most cases (6). In contrast to the preparation of islet allografts, purification with density gradients was not performed routinely for islet autografts because chronic pancreatitis is associated with fibrosis and reduced exocrine tissue mass, but purification has been applied more frequently since 2006 in cases where the digest volume was high (>20 cm3). Of 68 autologous islet preparations during 2006 to 2007, density gradient purification (using a COBE 2991 processor) was performed in 17 (25%) with a final purified pellet volume mean (±SD) of 22±10 cm3 (range, 3.5–40 cm3), whereas in 51 cases gradient purification was not carried out with a final pellet volume of 8±5 cm3 (range, 0.5–20 cm3) (P<0.05).

Several other changes in our protocol for autologous islet preparations occurred over the years. From 1977 to 1995, after excision, the pancreas was placed in cold (4°C) Hanks’ balanced salt solution for transportation to the laboratory. Since 1996, we have used modified University of Wisconsin (UW) solution (gluconic acid instead of lacto-bionic acid and high sodium, low potassium rather than the reverse).

Cold ischemia times did not differ by era. For our 2006 to 2007 islet autograft cases (n=66), the mean pancreas cold ischemia time was 58±24 min (range, 38–108 min). These data were in contrast to our own islet allograft series for 2000 to 2007 cases (n=33) where the mean pancreas cold ischemia time was 5.8±2.2 (range, 3–8 hr); and to that of the 1999 to 2006 cases (n=601) in the CITR database where the mean cold ischemia time before processing for alloislet isolation was 7.3±3.4 hr (range, 1–27 hr) (1). For our islet autograft cases, the time for islet preparation did not differ by era; for 2006 to 2008 cases the mean preparation time was 3.4±1.1 hr (range, 2–6 hr and 40 min). After preparation, autoislets were immediately transplanted in nearly all cases, in contrast to allogenic islets that were given fresh or cultured for 48 hr (16).

In regard to other changes in autoislet preparation, from 1977 to 1991 we used a stationary technique for collagenase digestion (5). In 1992, we began using the Ricordi chamber for collagenase digestion (6,10). Since 2000, we have not used any animal-derived products during islet isolation, such as fetal calf serum (9). From 1977 to 2000, we used crude collagenase preparations from Sigma or Worthington Companies (5, 6). During 2001 to 2006, we used a low-endotoxin collagenase (Liberase, Roche Company). In 2007, we switched to another low-endotoxin collagenase preparation (SERVA Company) that also met Good Manufacturing Practices standards. For islet purification, when performed, we used a COBE 2991 Processor.

In regard to transplantation, we administered heparin (70 mg/kg) intravenously just before embolization of purified or unpurified islets to the recipient’s liver by infusion over 30 to 60 min through a tributary to the portal vein by infusion, with intermittent measurement of portal venous pressure. Baseline portal pressure was nearly always 0 cm water. The infusion was stopped if the portal pressure went above 30 cm water. Immediate postinfusion portal pressure correlated with the tissue volume infused whether purified or unpurified. The postinfusion portal pressure for tissue volumes less than 5 (n=26), 5 to 15 (n=41) and more than 15 (n=18) mL were 3.5±2.8, 12.9±10.1, and 21.9±6.0 cm water (P<0.0001 for all comparisons, one-way analysis of variance).

For autografts, the range of IE per kilogram isolated was enormous in each era, 49 to 12,470 (median, 1375) for 1977 to 1990 (n=23); 111 to 17,035 (median, 4588) for 1991 to 1994 (n=15); 225 to 10,000 (median, 3121) for 1995 to 2000 (n=27); and 23 to 8558 (median, 3054) for 2001 to 2007 (n=107) cases; with corresponding means (±SD) of 2582±3194, 5296±4395, 3181±2523, and 3150± 1955 (P<0.05 for the 1991–1994 era versus the others, no other comparisons were statistically significant, Scheffe test). Low islet yields were more common than high islet yields. In the entire IAT series less than 2500 IE/kg was isolated in 64, 2501 to 5000 in 65, and more than 5000 in 35 cases. In only five cases more than 10,000 IE/kg was isolated. In contrast, for islet allografts as reported to CITR for 1999 to 2006, the mean IE/kg transplanted was 7485±2953 with a single donor (n=76), 13,228±approximately 2,000 with two (n=149) and 19,478±approximately 2600 with three donors (exhibit 3–8 in the CITR Report) (1).

IAT Function Classification

Of the 179 recipients with total or near TP, 173 had sufficient metabolic follow-up data for us to determine their islet autograft function over time. We considered islet function as full in recipients who were insulin independent, partial in euglycemic recipients on once-daily long-acting insulin, and failed in recipients on a standard insulin regimen. Because we did not routinely follow C-peptide levels in our patients before 2006, classification of graft function was dependent on insulin use for this analysis. To test the validity of our classification system, we looked at postoperative metabolic parameters (HbA1c and glucose tolerance stimulated C-peptide levels) in a subset of patients who underwent surgery between February 2006 and December 2007 for whom these data were available in our medical records. A total of 37 patients undergoing total or near-TP had metabolic testing at one or more time points between 3 and 12 months posttransplant (n=25 at 3 months, n=20 at 6 months, n=23 at 9 or 12 months). Of these patients, eight were classified as insulin independent (full graft function), 25 as partial graft function, and four as graft failure. All patients classified as partial function (by being only on once daily long-acting insulin) who were tested were indeed C-peptide positive, thus validating our classification model for the entire cohort. To assess metabolic differences between the partial function and full (insulin independent) function groups, we compared the mean stimulated C-peptide levels and mean HbA1C levels, using Student’s t test for statistical analysis. We also compared the proportion of patients in the two groups with an HbA1c of less than 7%, using Fisher’s exact test.

We estimated patient survival rates (all cases), full/partial (combined) islet function rates, and insulin independence rates using the Kaplan-Meier method (death censored for islet function and insulin-independence rates). We calculated islet autograft function rates overall, by era, by pancreatectomy classification and according to IE per kilogram transplanted. We calculated duration of function (full/partial) and duration of insulin independence in those who achieved such states. We compared the duration of function or insulin independence in our islet autograft recipients with published islet allograft data from the 2007 Report of the CITR (1).

RESULTS

After TP and an IAT, our patient survival rates were 95% at 1 year, 93% at 2 years, 85% at 5 years, and 76% at 10 years.

Of the 173 recipients with sufficient metabolic follow-up data, 57 (33%) had partial islet function and 55 (32%) had full islet function (insulin independent). Thus, a total of 112 (65%) had full or partial islet function at some posttransplant point.

The classification we used for islet function was based on the clinical criteria (insulin usage) for the entire series, but was justified by measurement of stimulated C-peptide levels and glycohemoglobin (HbA1cC), levels in the 2006 to 2007 cohort. Of those patients who received metabolic testing, all insulin-independent patients (n=8) were C-peptide positive (2 hr stimulated C-peptide levels ≥0.5 ng/mL) and all had an HbA1c less than 7% at each time point tested; one patient had an HbA1c of 6.6% at 1 year postoperatively, whereas the other six with testing at 1 year maintained HbA1c values less than or equal to 6.2%. Among the partial graft function patients (n=25, once daily insulin use), all were C-peptide positive at every time point tested, confirming graft function. The majority exhibited good metabolic control, with HbA1c levels less than 7% in 92% of patients (12/13) at 3 months, 93% (13/14) at 6 months, and 80% (12/15) at 9 to 12 months. Overall, 73% (15/22 with follow-up at 1 year) consistently maintained HbA1c levels under 7.0% at all time points tested through 1 year of follow-up.

The insulin-independent and partial graft function groups did not differ significantly in the proportion of patients maintaining an HbA1c less than 7% through 1 year posttransplant (P=0.14). Mean HbA1c levels at 3 to 12 months posttransplant were 5.8%±0.4% for insulin-independent patients (13 observations) and 6.6%±1.4% for the partial graft function patients (47 observations) (P=0.0015). Mean stimulated C-peptide levels at 3 to 12 months posttransplant were 3.9±1.5 ng/mL in the insulin-independent subjects (13 observations) compared with 2.7±1.3 ng/mL in those with partial graft function (43 observations) (P=0.017).

There were only a few cases of graft failure in this recent subset of IAT patients. In the four graft failure patients, two had an HbA1c more than or equal to 7%. Of the three with C-peptide levels documented, one patient was C-peptide positive (stimulated C-peptide of 1.0, 1.1, and 0.6 ng/mL at 6, 9, and 12 months) suggesting the presence of some graft function despite the need for a basal-bolus insulin regimen.

Islet function (full or partial) rates at 1 year posttransplant significantly (P<0.03) differed by era: 43% for 1977 to 1990 cases (n=24); 53% for 1991 to 1994 cases (n=16); 41% for 1995–2000 cases (n=27); and 71% for 2001 to 2007 cases (n=106). The higher rate of function in 2001 to 2007 cases than in earlier eras was not due to better islet yields because the IE per kilogram transplanted were not significantly higher than in the previous eras (see Methods section).

It should also be noted that the islet autograft function rates (partial/full) and insulin-independence rates were similar for patients undergoing one-stage TP (n=121), near-TP (n=17), or completion pancreatectomy (n=35): at 1-year, 60%, 53%, and 68% for function (P=0.6, Wilcoxin test); and 26%, 28%, and 31% for insulin independence (P=0.9). Thus, for analytical purposes we justified combining these subgroups into an overall group designated TP.

Islet function (full and partial combined) correlated (P<0.05) with islet yield: in recipients with less than 2500 IE/kg (n=64), 32% had islet function at 1 year; in recipients with 2501 to 5000 IE/kg (n=65), 79%; and in recipients with more than 5,000 IE/kg (n=35), 86%. The corresponding insulin-independence rates were 7%, 27%, and 63%, respectively (P<0.05). The CITR virtually never reported insulin independence in recipients with less than 5000 allogenic IE/kg.

For patients who had full or partial autoislet function in our entire series (all four eras), we compared the persistence of that function with that of islet allografts that functioned in the CITR analysis of 1999 to 2006 recipients (Fig. 1). In our autograft recipients with islet function at some point (full and partial combined), 85% still had islet function at 2 years posttransplant; of the 262 CITR islet allograft alone recipients who had partial islet function, only 66% still had islet function at 2 years (exhibit 5–11 in the CITR Report (1)). (In our series, 68% still had autoislet function at 5 years and 57% at 10 years, but we cannot compare with CITR analyses because they do not go beyond 3 years posttransplant).

FIGURE 1.

FIGURE 1.

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Rates of loss of islet graft function or insulin independence (II) in University of Minnesota (MN) pancreatectomized recipients of an islet autotransplant (auto) with islet function (n=112) or II (n=55) versus in type 1 diabetic recipients of an islet allotransplant (allo) reported to the Collaborative Islet Transplant Registry (CITR) with islet function (n=262) or II (n=154).

The difference in long-term outcomes between our IAT recipients and CITR allograft recipients was even greater in regard to insulin independence rates: 74% of IAT recipients who became insulin independent were still so at 2 years posttransplant, versus only 45% of the 154 CITR allograft recipients who initially became insulin independent (exhibit 5–14 in the CITR Report (1)). (In our series, 46% were still insulin independent at 5 years and 28% at 10 years, but again, CITR analyses do not go beyond 3 years posttransplant).

DISCUSSION

In our series, islet autografts that function (>50%, a rate correlated with islet yield) are fairly persistent, with more than half of these still functioning at 10 years. We do not think we overestimated islet autograft function rates by clinical assessment of insulin regimens, because all patients classified with partial function who were tested were C-peptide positive. Indeed, we could find a patient classified as an autograft failure who was C-peptide positive, and by allograft criteria would have been classified by CITR as having function. Further studies of “failed” islet autografts will reveal the true incidence of C-peptide positivity and whether any differences exist in glycemic control between those who are or not positive.

The main outcome difference between autografts and allografts is the durability of insulin independence; of our IAT recipients who became insulin independent, nearly half were still off insulin at 5 years and more than a quarter at 10 years. In contrast, in the islet allograft recipients immunosup-pressed with the Edmonton protocol, only 10% were still insulin independent at 5 years (3).

Our IAT results belie the hypothesis that the portal vein/hepatic environment is inherently hostile to islets. Indeed, in our series, five IAT recipients had been insulin independent for more than a decade.

Since more than three quarter of islet allograft recipients maintain positive C-peptide levels long term, even after becoming insulin-dependent again, rejection seems an unlikely explanation for their metabolic decline. It is possible that the viable islet mass engrafted in allograft recipients is less than that in IAT recipients, even though the IE per kilogram count is higher for allogenic islets. But allogenic islets are usually not fresh, as opposed to islet autografts (which are nearly always transplanted immediately after isolation from pancreases subjected to only minutes of cold ischemia time). Autoimmunity may also be responsible for the sharper decline of islet allograft function in recipients with type 1 diabetes (13,14), a condition not present in our IAT recipients.

The absence of diabetogenic immunosuppression in our IAT recipients also allows a smaller beta-cell mass to be adequate. A few of our IAT recipients even have insulin independence despite receiving beta-cell mass (as measured by IE/kg) of less than a quarter of the mass usually transplanted into islet allograft recipients.

Islet allograft protocols need to try to incorporate as many of the circumstances favorable to IATs as possible for clinical application.

ACKNOWLEDGMENT

The authors thank Mary E. Knatterud for editing the article.

This work was supported by The Collaborative Islet Transplant Registry, The General Clinical Research Center at the University of Minnesota, The Juvenile Diabetes Foundation International, The Indirect Cost Recovery Fund, and The J.B. Hawley Student Research Award.

Footnotes

Presented at the XXII International Congress of the Transplantation Society, Sydney, Australia, August 10–14, 2008.

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