Not So Crazy: Pancreas Transplants in Type 2 Diabetes Rising

Simultaneous pancreas-kidney transplants are increasingly performed in the United States in people with type 2 diabetes who also have chronic kidney disease, with outcomes similar to those of people with type 1 diabetes.

Traditionally, recipients of pancreas transplants have been people with type 1 diabetes who also have either chronic kidney disease (CKD) or hypoglycemic unawareness. The former group could receive either a simultaneous pancreas-kidney or a pancreas after kidney transplant, while the latter — if they have normal kidney function — would be eligible for a pancreas transplant alone.

But increasingly in recent years, patients with type 2 diabetes and CKD have been receiving simultaneous pancreas-kidney transplants, with similar success rates to those of people with type 1 diabetes.

Such candidates are typically sufficiently fit, not morbidly obese, and taking insulin regardless of their C-peptide status, said Jon S. Odorico, MD, professor of surgery and director of pancreas and islet transplantation at the University of Wisconsin Transplant Program, Madison.

"One might ask: Is it a crazy idea to do a pancreas transplant for patients with type 2 diabetes? Based on the known mechanisms of hyperglycemia in these patients it might seem so," he said, noting that while individuals with type 2 diabetes usually have insulin resistance, many also have relative or absolute deficiency of insulin production.

"So by replacing beta-cell mass, pancreas transplantation address this beta-cell defect mechanism," he explained when discussing the topic during a symposium held June 26 at the virtual American Diabetes Association (ADA) 81st Scientific Sessions.

Arguments in favor of simultaneous pancreas-kidney transplant in people with type 2 diabetes and CKD include the fact that type 2 diabetes is the leading cause of kidney disease in the United States — roughly 50%-60% of candidates on the kidney transplant waiting list also have type 2 diabetes — and that kidney transplant alone tends to worsen diabetes control due to the required immunosuppression.

Moreover, due to a 2014 allocation policy change that separates out simultaneous pancreas-kidney from kidney transplant alone donor organs, waiting times are shorter for the former and kidney quality is generally better than for kidney transplant alone, unless a living kidney donor is available.

And, Odorico added, "adding a pancreas to a kidney transplant does not appear to jeopardize patient survival or kidney graft survival in appropriately selected patients with diabetes." However, he also noted that because type 2 diabetes is so heterogeneous, ideal candidates for simultaneous pancreas-kidney transplant are not yet clear.

Currently, people with type 2 diabetes account for about 20% of those receiving simultaneous pancreas-kidney transplants and about 50% of pancreas after kidney transplants. Few pancreas transplants alone are performed in type 2 diabetes because those individuals rarely experience severe life-threatening hypoglycemia, Odorico explained.

Criteria Have Shifted Over Time, C-peptide Removed in 2019

In an interview with Medscape Medical News, symposium moderator Peter G. Stock, MD, PhD, surgical director of the Kidney and Pancreas Transplant Program at the University of California, San Francisco, said he agreed that "it's a surprising trend. It doesn't make intuitive sense. In type 1 diabetes, it makes sense to replace the beta cells. But type 2 is due to a whole cluster of etiologies...The view in the public domain is that it's not due to the lack of insulin but problems with insulin resistance and obesity. So it doesn't make a whole lot of sense to give you more insulin if it's a receptor problem."

But Stock noted that because in the past diabetes type wasn't always rigorously assessed using C-peptide and antibody testing, which most centers measure today, "a number of transplants were done in people who turned out to have type 2. Our perception is that everybody who has type 2 is obese, but that's not true anymore."

Once it became apparent that some patients with type 2 diabetes who received pancreas transplants seemed to be doing well, the pancreas transplantation committee of the United Network for Organ Sharing (UNOS) established general criteria for the procedure in people with diabetes. They had to be taking insulin and have a C-peptide value of 2 ng/mL or below, or taking insulin with a C-peptide greater than 2 ng/mL and a body mass index less than or equal to the maximum allowable BMI (28 kg/m² at the time).

Stock, who chaired that committee from 2005 to 2007, said: "We thought it was risky to offer a scarce pool of donor pancreases to people with type 2 when we had people with type 1 who we know will benefit from it. So initially, the committee decided to limit pancreas transplantation to those with type 2 who have fairly low insulin requirements and BMIs that are more in the range of people with type 1. And lo and behold the results were comparable."

Subsequent to Stock's tenure as chair, the UNOS committee decided that the BMI and C-peptide criteria for simultaneous pancreas-kidney were no longer scientifically justifiable and were potentially discriminatory both to minority populations with type 2 diabetes and people with type 1 diabetes who have a high BMI, so in 2019 they removed them.

Individual transplant centers must follow UNOS rules, but they can also add their own criteria. Some don't perform simultaneous pancreas-kidney transplants in people with type 2 diabetes at all.

At Odorico's center, which began doing so in 2012, patients with type 2 diabetes account for nearly 40% of all simultaneous pancreas-kidney transplants. Indications there include age 20-60 years, insulin dependent with requirements less than 1 unit/kg/day, CKD stage 3-5, predialysis or on dialysis, and BMI < 33 kg/m².

"They are highly selected and a fairly fit group of patients," Odorico noted.

Those who don't meet all the requirements for simultaneous pancreas-kidney transplants may still be eligible for kidney transplant alone, from either a living or deceased donor, he said.

Stock's criteria at UCSF are even more stringent for both BMI and insulin requirements.

SPK Outcomes Similar for Type 1 and Type 2 Diabetes: Emerging Data

Data to guide this area are accumulating slowly. Thus far, all studies have been retrospective and have used variable definitions for diabetes type and for graft failure. However, they're fairly consistent in showing similar outcomes by diabetes type and little impact of C-peptide level on patient survival or survival of either kidney or pancreas graft, particularly after adjustment for confounding factors between the two types.

In a study from Odorico's center of 284 type 1 and 39 type 2 diabetes patients undergoing simultaneous pancreas-kidney transplant between 2006 and 2017, pretransplant BMI and insulin requirements did not affect patient or graft survival in either type. There was a suggestion of greater risk for post-transplant diabetes with very high pretransplant insulin requirements (> 75 units/day) but the numbers were too small to be definitive.

"It's clear we will be doing more pancreas transplants in the future in this group of patients and it's ripe for further investigation," Odorico concluded.

Beta Cells for All?

Stock added one more aspect. While of course whole-organ transplantation is limited by the shortage of human donors, stem cell-derived beta cells could potentially produce an unlimited supply. Both Stock and Odorico are working on different approaches to this.

"We're really close," he said, noting, "the data we get for people with type 2 diabetes undergoing solid organ pancreas transplant could also be applied to cellular therapy...We need to get a better understanding of which patients will benefit. The data we have so far are very promising."

Odorico is scientific founder, stock equity holder, scientific advisory board chair, and prior grant support recipient from Regenerative Medical Solutions. He has reported receiving clinical trial support from Veloxis Pharmaceuticals, CareDx, Natera, and Vertex Pharmaceuticals. Stock has reported being on the scientific advisory board of Encellin and receives funding from the California Institute of Regenerative Medicine and National Institutes of Health.

ADA 2021 Scientific Sessions. Presented June 26, 2021.

Miriam E. Tucker is a freelance journalist based in the Washington, DC, area. She is a regular contributor to Medscape, with other work appearing in The Washington Post, NPR's Shots blog, and Diabetes Forecast magazine. She is on Twitter: @MiriamETucker.

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