Treating Type 1 Diabetes by Pancreas Transplant Alone: A Cohort Study on Actual Long-term (10 Years) Efficacy and Safety : Transplantation

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Original Clinical Science—General

Treating Type 1 Diabetes by Pancreas Transplant Alone: A Cohort Study on Actual Long-term (10 Years) Efficacy and Safety

Boggi, Ugo MD1,2; Baronti, Walter MD3; Amorese, Gabriella MD2; Pilotti, Silvia MS1; Occhipinti, Margherita MD4; Perrone, Vittorio MD2; Marselli, Lorella MD, PhD3,5; Barsotti, Massimiliano MD6; Campani, Daniela MD7; Gianetti, Elena MD3; Insilla, Andrea Cacciato MD7; Bosi, Emanuele PhD3; Kaufmann, Emanuele MD1; Terrenzio, Chiara MD3; Vistoli, Fabio MD, PhD1,2; Marchetti, Piero MD3,5

Author Information
Transplantation 106(1):p 147-157, January 2022. | DOI: 10.1097/TP.0000000000003627

Abstract

Erratum

In the article “Treating Type 1 Diabetes by Pancreas Transplant Alone: A Cohort Study on Actual Long-term (10 Years) Efficacy and Safety” by Boggi et al, which published in the January 2022 issue of Transplantation, the thirteenth author’s name appears incorrectly as Emanuele Kaufmann. The correct spelling of the author’s name is Emanuele F. Kauffmann.

Transplantation. 106(5):e286, May 2022.

INTRODUCTION

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells in genetically predisposed individuals, leading to insulin deficiency and hyperglycemia.1,2 Although strategies for the management of this disease have remarkably improved over the years.1,3-5 T1D continues to be associated with acute (hypoglycemia and ketoacidosis) and chronic (retinopathy, nephropathy, neuropathy, and cardiovascular disease) complications, which impact on quality of life and reduce life expectancy.1,6,7 Although exogenous insulin administration remains the mainstay of T1D therapy,1,3-5 biological replacement of the lost beta cells in T1D (as achievable by whole pancreas or isolated islet transplantation) is the only available approach that can restore physiologically regulated insulin secretion and glucose levels.8-12 Both procedures are associated with rescue from acute diabetes complications and may lead to improvement and/or stabilization of the degenerative vascular sequelae due to chronic hyperglycemia.13-18 Pancreas transplantation is a major surgical intervention, offering high chances of long-term insulin independence8,9,19; islet transplantation is a relatively low-risk approach, with less durable outcomes.1,11,12,18 The 2 approaches are similarly associated with the potential morbidity due to the immunosuppression therapies necessary to avoid graft rejection and/or recurrence of T1D autoimmunity.8-12,20

The first case of a whole pancreas transplantation was reported in 1966,21 and since then >80 000 cases have been reported to the International Pancreas Transplant Registry.22,23 Based on renal function, pancreas transplantation can be performed into 3 different categories of recipients8-10,24-26: patients with diabetes with chronic kidney failure should receive both a pancreas and a renal graft (simultaneous pancreas kidney transplantation); posturemic (after functioning kidney transplantation) diabetic subjects could benefit of a pancreas after kidney transplantation (PAK); selected diabetic individuals with maintained function of the native kidneys may receive a pancreas graft alone (PTA) if they face poor glycemic control despite optimal insulin therapy, experience problematic hypoglycemia, and/or suffer from progressive chronic complications of diabetes. Relevant work using single institution experiences, multicenter results, or registry data have described the outcomes of PTA in large patient series.8,9,22-24 However, the availability of sufficiently detailed results on the actual long-term outcomes of PTA in well-characterized T1D cohorts remains limited, and the debate on whether PTA is a profitable approach in T1D is still ongoing.1,8-10,27-29 To shed light on this relevant issue, here we describe the results achieved in a group of 66 T1D subjects who received a PTA at our Institution and were all followed for 10 y. Patient survival, graft function (defined according to recently published recommendations),29 and the trajectory of the native kidney function are the main outcomes we report. Recipients with functioning or lost pancreas graft function were also compared in terms of differences in key metabolic and renal features. This is the first comprehensive and detailed study on PTA outcomes in a reasonably large group of T1D subjects all followed for a whole decade.

RESEARCH DESIGN AND METHODS

Subjects

From May 1996 to May 2018, 392 pancreas transplant procedures have been performed at our institution, of which 255 were simultaneous pancreas and kidney transplants (including 28 with the kidney from a living donor) and 30 were pancreas after kidney transplants. The remaining 107 cases were PTA. Out of these latter, we selected 66 consecutive type 1 diabetic patients transplanted between April 2001 and December 2007, so that data could be analyzed after an actual posttransplant follow-up of 10 y in all of them. Diagnosis of T1D was confirmed on the basis of age at diabetes onset, low/undetectable fasting C-peptide values (around 0.2 nmol/L in 3 patients, between 0.1 and 0.2 nmol/L in 2 patients and from 0.0 to 0.1 nmol/L in all the others), and/or positivity of anti-GAD autoantibodies (Table 1). Additional clinical characteristics of the subjects in this cohort are also reported in Table 1. Subjects with pancreas retransplant or previous failed islet transplantation were not included. Variable proportions of the individuals considered in the present study have made part of previously published reports, focusing on selected outcomes after shorter follow-up periods.15,16,30 The study has been conducted with the approval of the local Ethics Committee.

TABLE 1. - Main clinical characteristics of type 1 diabetic subjects at the time of pancreas transplant
Subject Sex BMI (kg/m2) Age at diabetes onset (y) Diabetes duration (y) Age at PTA (y) C-peptide (nmol/L) Anti-GAD Ab (U/ml)a HbA1c (mM/M) Insulin dose (UI/d) eGFR UA
#1 M 26.9 12 32 44 0.007 0.17 67 44 61.0 Mic
#2 M 25.0 10 21 31 0.00 0.00 39 38 83.0 Mic
#3 F 20.8 8 21 29 0.00 0.95 88 36 109.0 N
#4 F 22.7 10 44 54 0.00 0.31 72 36 95.8 N
#5 F 22.6 6 21 27 0.00 2.12 124 51 98.5 M
#6 M 21.1 17 12 29 0.00 8.35 90 63 50.0 N
#7 F 21.6 14 14 28 0.00 NA 73 40 99.3 Mic
#8 M 28.4 11 42 53 0.00 0.00 79 54 66.4 N
#9 F 20.6 5 45 50 0.00 NA 70 32 94.0 N
#10 M 23.5 22 19 41 0.00 57.8 64 52 113.2 N
#11 M 26.5 5 27 32 0.00 NA 80 60 103.9 Mic
#12 M 19.0 3 28 31 0.003 0.00 87 45 89.5 Mic
#13 F 17.7 15 18 33 0.036 3.94 110 60 102.4 Mac
#14 M 24.1 17 23 40 0.016 0.54 56 76 87.0 Mac
#15 F 27.8 13 18 31 0.125 0.16 96 41 74.7 Mac
#16 M 22.2 41 19 60 0.155 0.26 69 38 91.5 N
#17 M 20.3 9 31 40 0.099 NA 69 40 59.7 Mac
#18 F 18.4 15 18 33 0.026 24.8 67 36 102.2 N
#19 F 16.7 18 14 32 0.00 NA 107 16 106.6 N
#20 F 22.2 12 29 41 0.00 0.24 60 40 94.9 Mac
#21 M 30.8 13 30 43 0.039 0.10 68 60 58.8 Mac
#22 F 26.7 14 32 46 0.023 75.44 81 44 82.1 N
#23 F 24.0 25 24 49 0.00 2.29 85 58 112.9 N
#24 M 26.9 14 18 32 0.016 0.35 95 52 119.1 N
#25 M 23.4 2 29 31 0.00 0.10 80 40 92.6 Mac
#26 F 25.3 10 26 36 0.00 0.00 34 NA 86.3 N
#27 F 26.1 10 26 36 0.016 0.13 80 36 69.9 N
#28 F 22.8 11 16 27 0.00 0.15 80 38 79.2 Mac
#29 M 21.1 32 3 35 0.211 9.84 77 32 94.7 N
#30 M 24.2 22 11 33 0.036 15.6 67 37 91.5 N
#31 F 25.0 21 12 33 0.029 15.3 62 40 60.8 N
#32 F 23.0 13 13 26 0.00 14.1 66 40 80.4 N
#33 M 21.6 12 27 39 0.00 0.00 96 42 90.5 Mac
#34 M 28.4 14 26 40 0.009 0.16 9.6 55 102.5 Mic
#35 F 24.8 12 31 43 0.201 0.00 54 24 47.5 Mic
#36 M 25.3 12 26 38 0.023 0.00 83 70 42.4 Mac
#37 F 23.2 10 26 36 0.069 91.7 99 33 100.6 N
#38 F Na 7 45 52 0.231 0.00 109 25 50.2 N
#39 M 29.8 2 41 43 0.023 0.11 68 50 64.0 Mic
#40 F 24.7 14 25 39 0.00 1.10 63 46 99.0 Mic
#41 F 21.2 12 17 29 0.009 2.54 57 42 105.1 Mic
#42 F 25.0 12 17 29 0.013 0.15 67 16 125.6 N
#43 F 22.1 7 34 41 0.043 0.27 88 42 52.6 Mac
#44 M 23.4 9 25 34 0.016 0.12 65 50 64.9 Mic
#45 M 27.9 7 25 32 0.00 0.13 88 55 125.2 Mic
#46 F 27.0 24 17 41 0.062 55.8 81 55 48.8 Mac
#47 M 21.6 7 22 29 0.013 0.00 77 47 110.3 Mic
#48 M 23.0 12 26 38 0.013 NA 100 38 52.0 Mac
#49 F 24.1 14 24 38 0.012 1.11 93 46 59.1 Mic
#50 M 23.1 3 39 42 0.082 0.12 50 43 123.9 N
#51 M 26.1 12 14 26 0.046 2.97 65 50 88.8 N
#52 F 24.8 37 8 45 0.076 5.91 93 35 88.8 N
#53 F 21.1 13 36 49 0.007 0.15 50 70 94.5 N
#54 F 25.7 29 8 37 0.010 26.1 99 37 92.4 N
#55 M 21.2 13 22 35 0.00 41.4 67 36 75.7 Mic
#56 M 20.8 18 27 45 0.013 0.00 74 48 125.5 Mic
#57 F 20.4 9 24 33 0.046 1.61 79 44 101.4 N
#58 M 22.1 40 19 59 0.00 4.43 74 50 91.8 Mic
#59 M 26.2 21 23 44 0.007 NA 51 50 89.4 Mic
#60 F 27.4 13 17 30 0.00 0.00 79 50 67.6 Mac
#61 M 23.0 40 16 56 0.089 7.45 77 48 148.7 N
#62 F 20.4 8 26 34 0.023 NA 75 42 79.0 Mic
#63 F 23.0 16 24 40 0.020 NA 115 24 78.7 Mac
#64 F 23.6 16 15 31 0.00 NA 80 43 69.5 N
#65 F 26.1 8 34 42 0.079 0.00 81 54 83.6 N
#66 F 21.0 5 32 37 0.00 0.14 70 61 94.0 Mic
Males 30 N 30 Mic
Females 36 16 Mac 20
Mean 23.6 14.2 23.9 38.1 0.033 9.33 77 44.6 87.0
SD 2.9 8.8 9.1 8.2 0.066 19.74 6 11.8 22.5
aAntiGAD Ab positive if >1.0 U/ml.
BMI, body mass index; eGFR, estimated glomerular filtration rate in mL/min/1.73m2; F, female; M, male; Mac, macroalbuminuria; Mic, microalbuminuria; N, normoalbuminuria; PTA, pancreas transplant alone; UA, albuminuria.

Nineteen patients (28%) were considered for PTA mainly because of glycemic lability [of whom, the majority (14, 74%) had hypoglycemia unawareness]; most subjects also exhibited varying degrees of single or combined chronic diabetes complications, including diabetic nonproliferative or laser treated diabetic retinopathy (49 patients), peripheral neuropathy (29 patients), and autonomic neuropathy causing gastroparesis (6 patients). The indications for PTA are summarized in Table S1, SDC, https://links.lww.com/TP/C107. At the time of PTA, the estimated glomerular filtration rate (eGFR, calculated by the use of the Modification of Diet in Renal Disease equation (31) was ≥90 mL/min/1.73 m2) in 33 (50.0%) patients, 60–89 mL/min/1.73 m2 in 24 (36.4%), and 50–59 mL/min/1.73 m2 in 6 (9.1%) subjects. In the remaining 3 patients, eGFR at the time of transplant ranged 42.4–48.0 mL/min/1.73 m2 (Table 1). Normoalbuminuric, microalbuminuric, and macroalbuminuric subjects, identified by routine methods (32), were 30 (45.5%), 16 (24.2%), and 20 (30.3%), respectively (Table 1).

Brain dead pancreas donors had the following main clinical characteristics: age 27.8 ± 11.9 y; gender 49 males and 17 females; and body mass index (BMI) 23.2 ± 3.1 kg/m2. Human leukocyte antigen-A and human leukocyte antigen-B mismatching was 2.8 ± 0.9 (range 1–4). Mean pancreas cold ischemia time was 11.5 ± 0.25 h.

Methods

Description of the surgical pancreas transplantation procedures as used at our Institution have been detailed previously.19,30 In short, all grafts were placed in the space behind the ascending colon and its mesentery. The enteric-portal drainage approach or the enteric-systemic drainage technique was used to handle the exocrine and endocrine pancreas secretions, based on the operators’ decision.30 The immunosuppressive induction treatment consisted of high-dose steroids plus basiliximab (20 mg) (Simulect, Novartis, Basel, Switzerland) or a single steroid bolus plus antithymocyte globulin (1 mg/kg/d) (Thymoglobulin, Genzyme Corporation, Cambridge, MA). The same maintenance therapy, including tacrolimus (Prograf, Astellas Pharma, Tokyo, Japan), mycophenolate mophetil (MMF, CellCept, Roche, Basel, Switzerland) or mycophenolic acid (EC-MPA, Novartis, Basel, Switzerland), and steroids (tapered to 5 mg at 3 mo posttransplant), was given to all recipients. The dose of tacrolimus was adjusted to maintain blood through levels of 10–15 ng/mL during the first weeks and progressively tapered over the time. In the present series, posttransplant trough tacrolimus concentrations (ng/mL) were 9.6 ± 1.8 at 1 mo, 9.2 ± 1.6 at 1 y, 8.4 ± 1.5 at 5 y, and 8.0 ± 1.2 at 10 y. MMF or EC-MPA was given at the highest tolerated dose, mainly based on hematologic and/or gastrointestinal toxicity. Initial doses were of 2 g/d of MMF and 1440 mg/d of EC-MPA, which at 10-y posttransplant ranged 0.5–1.5 g/d and 360–1080 mg/d, respectively. Additional prophylactic strategies were performed as previously reported.30

Among the clinical and biochemical parameters acquired on a regular basis, the following were used for the purposes of the present study: fasting plasma glucose, fasting C-peptide, glycated hemoglobin A1c (HbA1c), creatinine, and albuminuria. As mentioned earlier, eGFR was calculated by the use of the Modification of Diet in Renal Disease equation,31 and assessment of albuminuria/proteinuria was based on accepted and standardized procedures.32

Definition of Pancreas Transplant Outcomes

Pancreas graft outcomes were defined according to recently published criteria.29 Optimal pancreas graft function means normal or near-normal glycemic control without severe hypoglycemia or requirement for insulin or other antihyperglycemic therapy, and with an increase over pretransplant measurement of C-peptide. Definition of good graft function requires HbA1c <7.0% without severe hypoglycemia and with a significant (>50%) reduction in insulin requirements and restoration of clinically significant C-peptide production in comparison with pretransplant values. Marginal function is defined by failure to achieve HbA1c <7.0%, the occurrence of any severe hypoglycemia, or <50% reduction in insulin requirements when there is restoration of clinically significant C-peptide production documented by improvement in hypoglycemia awareness/severity, or glycemic variability/lability. Finally, pancreas graft failure is defined by the absence of any evidence for clinically significant C-peptide production. According to these definitions, optimal and good functional outcomes are considered successful clinical outcomes.29

Statistical Analysis

Data are presented as mean ± SD. Statistical analyses were conducted with R (R Core Team, 2017). Comparisons of results were performed by the 2-tailed Student’s t test for paired or unpaired data, or by the ANOVA analysis followed by the Bonferroni correction, as appropriate. Correlation tests were conducted using the Pearson’s product moment correlation coefficient (2-sided) with multiple regression models built taking into account patients’ major clinical variables.

RESULTS

Perioperative Outcomes

The enteric-portal or the enteric-systemic drainage approach was used in 50 (76%) and 16 (24%) patients, respectively. In the present series, repeat surgery was necessary in 9 (13%) patients; reasons were bleeding in 4 subjects (6%), occlusive vascular thrombosis in 3 individuals (4.5%), and hyperacute rejection in the remaining 2 recipients (3%). Induction immunosuppression was based on basiliximab in 48 (72.7%) patients or antithymocyte globulin in 18 (27.3%) cases. Clinically relevant bacterial infections during the postsurgical hospital period were observed in 5 patients, which resolved after appropriate antibiotic therapy. Inpatient stay varied according to the occurrence of these perioperative events, and was 21.2 ± 10.5 d.

Patients’ Survival

At 10 y after PTA, patients’ survival was 92.4% (61/66 subjects) (Figure 1). Five patients died during the 10-y follow-up period, for an overall mortality of 7.6% (0.76% per y). Causes of death were infectious disease in 2 cases (after 5 mo and 2.5 y from transplantation) and cardiovascular disease in the remaining 3 cases (after 8 y in 1 of them and 9 y in the other 2). In 3 subjects, death occurred with the pancreas graft still functioning. There was no significant difference in patients’ survival based on the type of drainage (enteric-portal: 46/50, 92.0%; enteric-systemic: 15/16, 93.7%) or the induction immunosuppression (basiliximab: 45/48, 93.7%; antithymocyte globulin: 16/18, 88.9%).

F1
FIGURE 1.:
Patient and pancreas survival after PTA. Patient (upper black line) and pancreas (lower dashed line) survival over 10 y follow-up in 66 subjects with type 1 diabetic and with PTA. Pancreas survival includes grafts with optimal function and graft with good function (n: 2, passed from optimal to good function at 1 and 8 y after transplantation). Functional definition was according to Ref. 29. PTA, pancreas transplant alone.

Pancreas Graft Survival

Based on recently provided criteria (29), of the 61 recipients (92.4%) who were alive at the end of the 10-y follow-up period, 35 (57.4%) had optimal graft function (normoglycemia and insulin independence) and 2 (3.2%) had good graft function (HbA1c <7.0%, no severe hypoglycemia, >50% reduction in insulin requirements, and restoration of clinically significant C-peptide production) (Figure 1). These 2 subjects had passed from optimal to good function at 1 and 8 y post-PTA. Therefore, in the present cohort, optimal or good pancreas survival of the transplanted pancreas was observed in 37 subjects (60.4%). As shown in Figure 1, 9 cases (13%) of all graft losses occurred in the first year posttransplant, due to biopsy-proven hyperacute or acute rejection. After the first 12 mo, the proportion of graft loss was 2.75% per y (Figure 1). Causes of pancreas graft loss were biopsy-proven acute/chronic rejection in 12 recipients, undefined in the remaining cases. Fasting plasma glucose values, HbA1c levels, and fasting C-peptide concentrations before and after transplantation of the 37 patients with long-lasting graft function are reported in Figure 2A–C, showing sustained normalization of glucose metabolism parameters and restoration of appropriate endogenous beta cell function. The functional outcome of pancreatic grafts trended better in the enteric-portal than the enteric-systemic group (30/46, 65.4% versus 7/15, 46.7%), and in the antithymocyte globulin (ATG) than the basiliximab induction therapy group (11/14, 78.6% versus 32/47, 68.1%), without reaching statistical significance.

F2
FIGURE 2.:
Metabolic outcome after PTA. Fasting plasma glucose (A), HbA1c (B), and fasting C-peptide (C) in subjects with type 1 diabetic pretransplant (pre-Tx, n: 66), with successful pancreas graft function at 5 y (n: 45) and 10 y (n: 37) post-Tx, or failed pancreas graft function at 10 y post-Tx (available in n: 20 subjects). *P < 0.01 vs Pre-Tx and failed post-Tx. HbA1c, glycated hemoglobin; PTA, pancreas transplant alone.

We also measured parameters of glycemic control at 10 y since transplantation in 18 patients with functional loss of the transplanted pancreas, which showed, as expected, significantly higher blood glucose and HbA1c levels (Figure 2A–C).

Effects on the Native Kidneys

The course of renal function in the PTA recipients in the current cohort is reported in Figure 3. Over the 10-y follow-up, 4 patients (6.0%) developed end-stage renal failure (stage 5, eGFR <15 mL/min/1.73 m2), with start of dialysis at 1, 2, 8, and 9 y since transplant (one of them then received a kidney graft from a living donor 4 y after the beginning of dialysis). The respective eGFR before transplant were 48.8, 52.0, 79.2, and 148.7 mL/min/1.73 m2. Of them, 1 patient died with a functioning pancreas graft shortly after the start of dialysis due to myocardial infarction, and the other 3 recipients were insulin-independent at 10 y posttransplant. Two additional patients (3.0%) showed stage 4 kidney failure (eGFR 15–30 mL/min/1.73 m2) at the 10-y posttransplant assessment (both were insulin-independent). Their pretransplant eGFR values were 58.8 and 94.0 mL/min/1.73 m2. Of the 6 patients who developed stage 4 or stage 5 kidney disease (altogether 9.1% of the initial cohort), 3 had an eGFR <60 mL/min/1.73m2 and were macroalbuminuric at time of transplant. However, the 3 additional patients with eGFR <60 mL/min/1.73m2 and macroalbuminuria before transplant at the time of transplant remained substantially stable. Although specific statistical analysis could not be conducted due to the small number of cases, these results show that transplanted patients with eGFR <60 mL/min/1.73 m2 and macroalbuminuria before surgery had a 10-y posttransplant end-stage renal disease rate of 50% (3/6).

F3
FIGURE 3.:
Estimated glomerular filtration rate (eGFR) before, at 1, 5, and 10 y since pancreas transplantation in subjects with functioning pancreas graft. Results are provided for the whole cohort (upper panel) and according to pretransplant eGFR of ≥90, 60–89, and <60 mL/min/1.73 m2 in the lower panels. TX, transplantation.

In the PTA recipients with 10-y functioning graft (n: 37), mean eGFR loss at 1 y after transplant was 14.9 ± 26.9 mL/min/1.73 m2. The decline was more marked at elevated pre-PTA eGFR and HbA1c values (Figure 3; Table 2). The average yearly eGFR reduction was apparently smaller (1.7 ± 2.5) in the period 1–10 y since transplantation, with the decline resulting correlated with the duration of diabetes (Table 2). After exclusion of the patients who developed stage 4 or 5 renal disease, recipients with successful PTA at 10 y (n: 32) showed an eGFR that changed from 87.2 ± 27.5 (pre-PTA) to 64.3 ± 20.0 (10 y since PTA) mL/min/1.73 m2 (P < 0.01). This corresponded to a yearly reduction of −2.3 ± 2.7 mL/min/1.73 m2. The eGFR trajectories in these patients are reported in Figure 3, according to pre-PTA values. We also checked kidney function before and at 10 y after transplantation in 7 patients who had experienced graft loss in the early weeks after grafting and discontinued any immunosuppressive therapy shortly afterward. In this small group of subjects, eGFR values decreased from 101.9 ± 17.5 to 77.1 ± 20.5 mL/min/1.73 m2 (P < 0.01), corresponding to a decline of −2.5 ±1.8 mL/min/1.73 m2 on an annual basis.

TABLE 2. - Linear correlation and multiple regression analyses of several pre-PTA clinical parameters with the decline of eGFR at 1 y posttransplant and the following 1-10 y in PTA recipients (n: 37) with functioning pancreatic graft at 10 y post-PTA
eGFR decline, 1 y eGFR yearly decline, 1–10 y
Linear correlation Multiple regression Linear correlation Multiple regression
Coefficient P Coefficient P Coefficient P Coefficient P
Sex 0.21 0.20 7.80 0.20 0.14 0.41 0.41 0.64
BMI 0.40 0.01 −0.35 0.74 0.06 0.71 / /
Age at diabetes onset 0.21 0.19 0.47 0.23 0.35 0.03 / /
Diabetes duration 0.14 0.38 0.33 0.35 0.41 0.01 0.10 0.04
Insulin daily dose 0.05 0.75 0.06 0.76 0.07 0.68 / /
HbA1c 0.49 0.001 0.55 0.007 0.07 0.92 / /
Pre-PTA eGFR 0.77 0.0000002 0.66 0.0001 0.27 0.09 0.01 0.61
Urinary albumin 0.03 0.19 / / 0.18 0.27 0.60 0.23
Variables with no coefficients (/) were excluded from the regression model due to collinearity. Variables with significant P-values (P ≤ 0.05) have their coefficients and P-values reported in bold.
BMI, body mass index; eGFR, estimated glomerular filtration rate in mL/min/1.73m2; HbA1c, glycated hemoglobin; PTA, pancreas transplantation alone.

Albuminuria data were available for 31/32 recipients with a functioning graft at 10 y posttransplantation. Before transplantation, there were 15 patients with normoalbuminuria, 8 with microalbuminuria and 8 with macroalbuminuria. As shown in Figure 4, 74% of the normoalbuminuric or microalbuminuric subjects remained stable, and 26% progressed towards a worse stage; conversely, 62.5% of the macroalbuminuric individuals showed a regression of albuminuria severity.

F4
FIGURE 4.:
Trajectories of albuminuria from pretransplant (pre-Tx) to 10 y posttransplant (post-Tx) in subjects with functioning pancreas graft. Ma-alb, macroalbuminuria; Mi-alb, microalbuminuria; N-alb, normoalbuminuria.

DISCUSSION

PTA may be indicated in selected type 1 diabetic individuals with maintained function of the native kidneys.9,24,25 This procedure represents around 10% of all the pancreas transplants, and its outcomes have improved significantly over the years.8,9,22-24 However, the relative benefits and risks of PTA are still matter of debate. The present study reports a detailed analysis of the major outcomes after PTA in a series of 66 type 1 diabetic subjects all carefully characterized before transplantation and accurately followed for 1 decade. In such a cohort, we found that actual patient survival at 10 y was 92.4%. A recent analysis of the International Pancreas Transplant Registry data shows that actuarial 10-y PTA patient survival (transplants performed in the 2001–2005 period) was 72.3%.22 An examination of the survival benefit of several solid organ transplants performed with the United Network for Organ Sharing database and the Social Security Administration Death Master File has reported that PTA can save 2.4 life-y per patient, compared to subjects waitlisted for the procedure.33 However, a key issue is if PTA impacts on life expectancy in comparison with nontransplant, insulin-based therapies in type 1 diabetic subjects. In our series, the rate of mortality was 0.76%, per y, which is similar to the values reported in studies assessing this parameter in a number of different T1D populations.34-38 However, in patients with microalbuminuria, macroalbuminuria and/or diabetic brittleness (which are features commonly found pretransplant in our T1D patients who received a PTA), the mortality rate increases 2–4 fold.34,38,39 Unfortunately, controlled trials to compare transplant versus nontransplant approaches in type 1 diabetic patients are difficult to plan, due to differences in clinical needs and ethical issues. Nevertheless, the results of the present study and data from the literature suggest, although indirectly, that PTA has a neutral or even positive effect on life expectancy in selected type 1 diabetic patients. Longer follow-up of PTA cohorts will add useful information in this regard.

According to recently published criteria,29 optimal and good pancreatic graft function at 10 y since transplantation was achieved in 60.4% of our PTA recipients, with a rate of insulin independence of 57.4%. As documented by the data of the International Pancreas Transplant Registry, PTA graft survival has progressively increased over time, due to reduced technical failures and immunological loss, reaching 40% at 10 y in the 2011–2005 cohort, and 70% at 3 y in the 2011–2016 series in the United States.22 Our results compare favorably with the data obtained in multicenter analyses,20,22,24,27 possibly due to more consistent surgical and medical procedures, as achievable in single-center experiences.40 Similar single-center improved results have been reported in the islet transplant field.41 More in general, our pancreas graft survival outcomes indicate that success rate of PTA can be apparently better than what commonly appreciated.20,22,27,28 We noticed a nonstatistically significant trend to better long-term pancreas graft function outcome with the enteric-portal than the enteric-systemic drainage (65.4% versus 46.7%). Registry results and systemic review data have previously shown that the 2 approaches provide similar patient and/or allograft survival for the majority of recipients.42,43 We also observed that pancreas graft survival was slightly, although not significantly, higher in the ATG versus basiliximab induction therapy (78.6% versus 68.1%). Some single-center studies have suggested ATG use to reduce graft rejection in pancreas transplantation, in comparison with basiliximab.44,45 As a matter of fact, most pancreatic graft recipients receive T-lymphocyte depleting induction therapy.46

Restoration of normoglycemia by endogenously regulated insulin release as achievable with beta cell replenishment (pancreas or islet transplantation) prevents acute complications of diabetes.7-12,17,18,20,47-51 In addition, successful PTA generally associates with stabilization or improvement of diabetic retinopathy, beneficial effects on diabetic neuropathy, and amelioration of heart morphology and function.9,15,16,20,47,48,52 Addressing the impact of PTA on chronic vascular diabetic complications was beyond the purpose of the present study. However, we focused on the impact of this procedure on the native kidneys, which is still debated. Early findings reported an apparent decline of creatinine clearance at 5 y post-PTA (from 108 ± 20 mL/min/1.73 m2 pretransplant to 74 ± 16 mL/min/1.73 m2).53 This action was probably due to the potential deleterious action of calcineurin inhibitors on the kidney.54,55 However, over time kidney function stabilized and at 10 y since transplantation histological lesions of diabetic nephropathy reversed.53 Multicenter studies involving large cohorts (>1000 patients) observed that 10 y after transplantation 20%–50% of PTA recipients had developed end-stage renal disease.56,57 The proportion was higher in subjects with eGFR <60 mL/min/1.73 m2 pretransplant and lower in more recent transplantation eras.56,57 In our present study, 6 PTA recipients (9%) developed stage 4 or 5 renal disease during the 10-y follow-up. Of them, 3 had eGFR <60 mL/min/1.73 m2 and were macroalbuminuric before transplantation. If the 6 type 1 diabetic patients with both eGFR <60 mL/min/1.73 m2 and macroalbuminuria pretransplant are excluded from the analysis, the rate of stage 4 or 5 kidney failure is 5%. Interestingly, in the other recipients with functioning pancreas graft at 10 y posttransplant, the mean yearly decline of renal function (−2.29 ± 2.69 mL/min/1.73 m2) was similar to that of a relatively small group of subjects of the present cohort, who had discontinued immunosuppression therapy due to early graft loss (−-2.5 ± 1.8 mL/min/1.73 m2). For the reasons mentioned earlier (differences in clinical needs and ethical issues), also in the case of eGFR changes, there is no controlled trial comparing PTA transplant versus nontransplant therapies in type 1 diabetic patients. However, the yearly eGFR decline observed in our series of long-term functioning PTA recipients is similar to that (−2.9 mL/min/1.73 m2, median value) reported in 244 type 1 diabetic individuals with eGFR ≥60 mL/min and followed for up to 18 y.58 In addition, these values compare favorably with that (−12.2 mL/min/1.73 m2) observed in nontransplanted type 1 diabetic patients who develop end-stage renal disease.59 This overall limited impact of PTA on native kidney function in our patients, together with the stabilization or improvement of albuminuria in the majority of them, may be due to several factors, including strict monitoring of risk factors and reduced targets of tacrolimus blood concentrations (around 8 ng/mL) during the follow-up, as well as genetic variability.60,61 Of interest, we observed a major reduction of eGFR in the first year post-PTA, confirming previous findings.53,62 This is likely due to functional changes, since we observed greater decline in subjects with higher pre-PTA eGFR. Such an overfiltration has been described in some individuals with T1D and has been attributed to the impact of hyperglycemia on several hemodynamic and renal factors.13,63 After the first year posttransplant, there was a relative stability of kidney function, suggesting that over the time the restored normoglycemia may play its beneficial effects.53,63,64 Yet, we found that duration of diabetes correlated with this later decline, suggesting a sort of negative legacy of this parameter even after transplantation. Specifically designed studies will have to be conducted to clarify these points, including the role of longer observations.

In conclusion, this study reports the detailed actual results of PTA in a cohort of well-characterized type 1 diabetic patients who were followed accurately long-term (10 y) since the transplantation procedure. After the early concerns65 and the successive discussions27,33 on the role of PTA, our present data further support pancreas transplantation alone to cure diabetes in clinically suitable type 1 diabetic patients.

ACKNOWLEDGMENTS

The authors are indebted with all the personnel who have assisted the patients during the period of the study reported in this article.

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