Noninvasive evaluation of donor and native pancreases following simultaneous pancreas–kidney transplantation using positron emission tomography/computed tomography

ABSTRACT

It is crucial to develop practical and noninvasive methods to assess the functional beta‐cell mass in a donor pancreas, in which monitoring and precise evaluation is challenging. A patient with type 1 diabetes underwent noninvasive imaging following simultaneous kidney–pancreas transplantation with positron emission tomography/computed tomography (PET/CT) using an exendin‐based probe, [¹⁸F]FB(ePEG12)12‐exendin‐4. Following transplantation, PET imaging with [¹⁸F]FB(ePEG12)12‐exendin‐4 revealed simultaneous and distinct accumulations in the donor and native pancreases. The pancreases were outlined at a reasonable distance from the surrounding organs using [¹⁸F]FB(ePEG12)12‐exendin‐4 whole‐body maximum intensity projection and axial PET images. At 1 and 2 h after [¹⁸F]FB(ePEG12)12‐exendin‐4 administration, the mean standardized uptake values were 2.96 and 3.08, respectively, in the donor pancreas and 1.97 and 2.25, respectively, in the native pancreas. [¹⁸F]FB(ePEG12)12‐exendin‐4 positron emission tomography imaging allowed repeatable and quantitative assessment of beta‐cell mass following simultaneous kidney–pancreas transplantation.

[18F]FB(ePEG12)12‐exendin‐4 PET/CT yielded successful noninvasive imaging of the donor and native pancreases in a case who underwent simultaneous kidney–pancreas transplantation. The noninvasive simultaneous evaluation demonstrated distinct accumulation in the donor and native pancreases.

1 | INTRODUCTION

Pancreas transplantation (PTx) restores endogenous insulin secretion in insulin‐dependent type 1 diabetes (T1D) ¹ , ² . Measuring the residual graft beta‐cell mass (BCM) is important in managing type 1 diabetes and in predicting transplantation outcomes ³ . Residual graft function can be determined by measuring the insulin secretion capacity ⁴ ; however, this method cannot distinguish between viable graft BCM and remnant beta‐cell function ³ , ⁵ , ⁶ , ⁷ , ⁸ , ⁹ , ¹⁰ . Therefore, the development of noninvasive methods to evaluate BCM function is warranted to improve the understanding of pathophysiology underlying graft failure and to reduce graft loss following transplantation ¹ , ² , ³ , ⁸ .

We reported a radioisotope‐labeled exendin‐4 probe conjugated with polyethylene glycol ([¹⁸F]FB(ePEG12)12‐exendin‐4: [¹⁸F]‐PEG‐Ex4) ¹¹ . A previous clinical trial demonstrated the safety of this probe and specific visualization of the pancreas using positron emission tomography (PET) ¹² , indicating that [¹⁸F]‐PEG‐Ex4 can be used in PET imaging of pancreatic beta cells in donor and native pancreases following transplantation.

Here we describe a successful, noninvasive, and simultaneous evaluation of the donor and native pancreases using [¹⁸F]‐PEG‐Ex4 PET.

2 | MATERIALS AND METHODS

2.1 | Case

The patient was a 46‐year‐old male who was diagnosed with type 1 diabetes at 8 years of age. The patient was 164.0 cm tall and weighed 44.0 kg. Recent HbA1c levels were 8.0%–11.0% (64–97 mmol/mol). He required daily insulin injections to manage severe hyperglycemia. He underwent surgery for vitreal hemorrhage at 39 and 40 years. At 43 years, hemodialysis was started for managing end‐stage renal failure caused by diabetic nephropathy. Despite using intermittent‐scanned continuous glucose monitoring, the serum glucose levels remained uncontrolled. After glucagon stimulation testing, urine and serum C‐peptide levels were >0.5 μg/day (0.166 nmol/day) and >0.05 ng/mL (16.6 pmol/L), respectively. Therefore, simultaneous pancreas–kidney transplantation (SPK) was performed at 46 years using donor organs after brain death (Data S1).

2.2 | [ ¹⁸F]‐PEG‐Ex4 PET/CT

The [¹⁸F]‐PEG‐Ex4 probe was synthesized as described previously ¹¹ , ¹² . Before imaging, 43.0 MBq [¹⁸F]‐PEG‐Ex4 was administered intravenously over 5 min. Whole‐body PET scan images were captured at 2 min per frame for six frames at 1 h and 3 min per frame for six frames at 2 h after administering [¹⁸F]‐PEG‐Ex4 using an integrated PET/computed tomography (PET/CT) scanner (Discovery IQ; GE Healthcare, Waukesha, WI). Organ accumulation of [¹⁸F]‐PEG‐Ex4 was quantified using the mean and maximum standardized uptake values in Advantage Workstation server 3.2 (GE Healthcare, Chicago, IL) ¹¹ . This study was approved by Ethics Committee of Kyoto University Graduate School of Medicine and University Hospital (C1480) and conformed to the provisions of the Declaration of Helsinki.

3 | RESULTS

3.1 | [ ¹⁸F]‐PEG‐Ex4 PET/CT imaging after simultaneous pancreas–kidney transplantation

[¹⁸F]‐PEG‐Ex4 imaging was performed 12 weeks after simultaneous pancreas–kidney transplantation. Serum aspartate aminotransferase and alanine transaminase levels were 13 and 16 U/L, respectively. The estimated glomerular filtration rate and HbA1c level were 48.9 mL/min/1.73 m² and 5.8%, respectively. At 1 and 2 h after [¹⁸F]‐PEG‐Ex4 administration, the transplanted pancreas was clearly visible in the right peritoneal cavity (Figures 1 and 2). Maximum intensity projection (MIP) imaging revealed distinct uptakes in the native and donor pancreases (Figure 1). Axial images revealed relatively heterogeneous uptakes within the native pancreas (Figure 2c,d), which were milder than those in the donor pancreas but higher than those in the liver and spleen. At 1 and 2 h after [¹⁸F]‐PEG‐Ex4 administration, the SUV_mean were 2.96 and 3.08, respectively, in the donor pancreas and 1.97 and 2.25, respectively, in the native pancreas. The SUV_mean ratios of the donor to native pancreas were 1.50 and 1.37 at 1 and 2 h, respectively, after [¹⁸F]‐PEG‐Ex4 administration. The SUV_mean of the donor kidney was ~20 times greater than that of the native kidneys. The SUV_max of the donor pancreas was 4.67 at 1 h and 4.24 at 2 h after [¹⁸F]‐PEG‐Ex4 administration. The SUV_max of the native pancreas was 2.98 at 1 h and 3.30 at 2 h after [¹⁸F]‐PEG‐Ex4 administration.

Figure 1.

Whole‐body maximum intensity projection (MIP) images of [¹⁸F]‐PEG‐Ex4. Front (a) and left lateral oblique (b) views of whole‐body MIP images 1 h after [¹⁸F]‐PEG‐Ex4 administration. Front (c) and left lateral oblique (d) views of whole‐body MIP images 2 h after [¹⁸F]‐PEG‐Ex4 administration. The white and blue arrows show the donor and native pancreases, respectively. The black arrowhead and the blue arrowhead show the donor and native kidneys, respectively.

Figure 2.

[¹⁸F]‐PEG‐Ex4 PET/CT images of the donor and native pancreases. Axial PET/CT images at the donor pancreas level (a) and native pancreas level (c) and coronal PET/CT images (e) 1 h after [¹⁸F]‐PEG‐Ex4 administration. Axial PET/CT images at the donor pancreas level (b) and native pancreas level (d) and coronal PET/CT images (f) 2 h after [¹⁸F]‐PEG‐Ex4 administration. The left panels show fusion images of PET and CT, and the right panels show PET images. The white and blue arrows show the donor and native pancreases, respectively. The black arrowhead and blue arrowhead show the donor and native kidneys, respectively.

3.2 | Insulin secretion capacity after simultaneous pancreas–kidney transplantation

Endogenous basal insulin secretion and glucose‐stimulated insulin secretion were observed in the donor pancreas. Urinary C‐peptide excretion was 25 μg/day (8.28 nmol/day) at 6 weeks after transplantation, which was undetectable before transplantation. From baseline to 6 min after a 1.0 mg glucagon stimulation test, serum C‐peptide levels increased from 3.74 to 7.92 ng/mL (1.24–2.62 nmol/L) and serum glucose levels increased from 99 to 118 mg/dL (5.50–6.55 mmol/L).

4 | DISCUSSION

This case shows that [¹⁸F]‐PEG‐Ex4 simultaneously but distinctively accumulates on PET in both the donor and native pancreases following SPK. In our previous study ¹² , the SUV_mean of the transplanted pancreas was comparable to that of healthy subjects (3.06 vs 3.19 ± 0.44 at 2 h after ¹⁸F‐PEG‐Ex4 administration) and consistent with the observed insulin secretion capacity after SPK. The SUV_mean of the native pancreas was consistently lower than that of the donor pancreas and healthy subjects, indicating the effectiveness of [¹⁸F]‐PEG‐Ex4 PET in performing reproducible and quantitative clinical assessments.

To the best of our knowledge, [¹⁸F]‐PEG‐Ex4 is the first probe that specifically targets GLP‐1R with [¹⁸F] labeling and PEGylation to improve pharmacokinetics and probe delivery to beta cells and to reduce interference from unspecific uptakes from surrounding organs, such as the kidneys ¹¹ . The successful visualization of the donor pancreas using [¹⁸F]‐PEG‐Ex4 PET indicates the potential of this technique in imaging the donor pancreas. Furthermore, the simultaneous accumulation of [¹⁸F]‐PEG‐Ex4 within the donor and native pancreases can help in quantifying BCM; however, further clinical studies must validate these findings.

In this case, probe accumulation was observed in the native pancreas although the detection of large regions had a remarkably lower signal than the donor pancreas. This finding might be consistent with the reported presence of residual beta cells in postmortem studies and in the donor pancreases of patients with a long history of insulin‐dependent diabetes ¹³ , ¹⁴ . Nevertheless, human pancreatic exocrine cells exhibit limited expression of GLP‐1R ¹⁵ , ¹⁶ , which might partly contribute to pancreas signals on [¹⁸F]‐PEG‐Ex4 PET. Further investigations should be warranted in patients with type 1 diabetes, especially in those whose insulin secretion is completely deleted.

This study demonstrated the successful noninvasive imaging of the donor and native pancreases following simultaneous pancreas–kidney transplantation using [¹⁸F]‐PEG‐Ex4 PET/CT, resulting in simultaneous and distinct accumulation in the donor and native pancreases.

DISCLOSURE

N.I. received joint research grants from Daiichi Sankyo, Terumo, and Drawbridge Health, received speaker honoraria from Kowa, MSD, Astellas Pharma, Novo Nordisk Pharma, Ono, Nippon Boehringer Ingelheim, Takeda, and Mitsubishi Tanabe Pharma, and received scholarship grants from Kissei, Sanofi, Daiichi‐Sankyo, Mitsubishi Tanabe, Takeda, Japan Tobacco, Kyowa Kirin, Sumitomo Pharma, Astellas Pharma, MSD, Eli Lilly Japan, Ono, Sanwa Kagaku Kenkyusho, Nippon Boehringer Ingelheim, Novo Nordisk Pharma, Novartis Pharma, Teijin Pharma, and Life Scan Japan. The remaining authors have no conflicts of interest to disclose.

Approval of the protocol: The Committee of Kyoto University Graduate School and Faculty of Medicine and Kyoto University Hospital (C1480).

Informed consent: The written informed consent was obtained from the subject.

Approval date of Registry and the Registration No: May. 11, 2022, jRCT1051220023.

Animal studies: N/A.

Supporting information

Data S1 | The procedure of simultaneous pancreas–kidney transplantation