kidney transplant

Consensus criteria, education could boost pancreas transplantation uptake in diabetes

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The odds of undergoing a successful pancreas transplantation for people with diabetes have increased in recent years, but the number of adults undergoing the procedure is declining, according to a review article.

A study published in American Journal of Transplantation in 2016 detailed a steady increase in the survival rate of people who undergo a simultaneous pancreas and kidney transplant and those who have a pancreas transplant after a kidney transplant. The proportion of those who had a functioning pancreas after any type of transplantation also increased from 1999-2003 to 2009-2013.

Jonathan A. Fridell, MD, FACS

Pancreas transplantation success rates have increased in the past 20 years, but the number of adults undergoing the procedure in the U.S. has declined. A report published in Current Opinion in Organ Transplantation in 2016 found the number of pancreas transplantations taking place in the U.S. peaked in 2003 before steadily declining from 2004 to 2013.

The decline in surgery rates has continued in recent years. In a review published in The Journal of Clinical Endocrinology & Metabolism, Jonathan A. Fridell, MD, FACS, professor of surgery, chief of abdominal transplant surgery and director of pancreas transplantation at Indiana University School of Medicine, and colleagues wrote that from 2005 to 2021 in the U.S., the number of simultaneous kidney and pancreas transplantations declined 9%, pancreas transplantations after kidney transplantation declined 85%, and pancreas transplantations alone decreased by 63%. Similar declines have been observed in other countries as well.

“Kidney and pancreas transplantation have been a recognized standard of care for certain patient populations for more than 20 years, pancreas transplant alone for slightly less than that,” Fridell told Healio. “There isn’t a therapy that competes with them for the patients that have the right indications. Yet when we look at guidelines for management of patients with diabetic nephropathy and guidelines for patients with diabetes, most often these treatment pathways aren’t explored. I think it’s because there’s hope that there’ll be something better that comes along, there’s a belief that insulin therapy must be able to work and there is a concern that this is a potentially morbid operation.”

Healio spoke with Fridell about the benefits and risks of pancreatic transplantation for people with diabetes, factors behind the decline in transplantation in recent years, and reasons health care professionals should better educate people with type 1 or type 2 diabetes who may be candidates for the procedure.

Healio:Can you provide some background on pancreas transplantation as it pertains to people with diabetes? What are some of the benefits and risks of this procedure?

Fridell: Pancreas transplantation is not new. The first pancreas transplant was performed in the late 1960s at the University of Minnesota. In the operation, you add an extra pancreas, you don’t take out the original pancreas, you give them a second one. The point is if somebody is not making enough insulin to regulate their glucose, if you give them an extra pancreas, that one should make the insulin that they need. It’s very much like the way that we add a kidney when somebody is not making enough or good enough urine; that way we can get them out of renal failure and off of dialysis.

The risks are that it’s a major abdominal surgery. Any time you do an organ transplant, there’s a risk that the blood supply will clot off. For pancreas transplants, it’s probably slightly more common than for other types of transplants. Also, the pancreas is attached to the intestine, very rarely to the bladder, so there’s a risk that the attachments might leak. But all of these are uncommon complications.

Complications are typically graft-threatening, meaning that you can lose the pancreas because of them. They can be, but are not usually, life-threatening. And then there are the risks of lifelong immunosuppression. So, instead of the risk for diabetes where the patients might get vision loss or limb loss or loss of their kidney function, they trade that off for immunosuppression, which has toxicity, and puts patients at risk for opportunistic infections and cancers.

Most of the time we do pancreas transplants along with another organ, with the logic being that since they’re committed to lifelong immunosuppression for the other organ, they might as well not be diabetic. The vast majority of those are kidney transplants for diabetic nephropathy or diabetic kidney disease. The very select group of patients that qualify for a transplant are those patients who need a kidney, or for patients with life-threatening complications of diabetes, with the most common one of those being hypoglycemia unawareness. In that group of patients, we would also include patients who’ve had their pancreas removed for noncancerous reasons, like chronic pancreatitis.

Healio:Could pancreas transplantation be performed in a wider population of people with diabetes?

Fridell: Originally, this operation was reserved for patients with specifically type 1 diabetes, due to the risk for technical complications. We used to also restrict it to fairly straightforward candidates — so younger recipients with not a lot of vascular disease and not very overweight.

Recently, we’ve expanded the number of people who are suitable for this operation. We’re offering it to older patients, which is good because our recipient population is aging. Most programs offer into age 50 to 59 years, many programs into age 60 to 69 years, and very few, but some programs up into age 70 years and older. Patients with higher BMI are also being offered transplants.

What’s really interesting is nowadays we’re also offering it to patients with type 2 diabetes. That’s actually becoming a very common reason, to get a kidney and a pancreas transplant together for type 2 diabetes.

Healio:Is there a reason diabetes care professionals are hesitant to recommend a pancreas transplant for patients?

Fridell: There’s a long memory for the early history of pancreas transplantation from when this operation was first introduced. At that time, there were issues and complications during the period when we were figuring out how to do the operation and fine-tuning the surgical techniques, preservation solutions, postoperative management and immunosuppression, as was the case for every other type of transplant that we’ve done. There’s a period of learning and figuring steps out, and there’s a long memory for what pancreas transplants looked like during these early years and probably up until the late 1990s. But we’ve changed the technical aspects of the operation. We have better preservation solutions, immunosuppression has evolved, and we’ve become more experienced. We’re better at understanding complications and, therefore, predicting and preventing complications. Graft survival has improved significantly, and the technical graft loss has gone way down.

Healio:Why has there been a decline in the number of pancreas transplantation procedures over the past 20 years?

Fridell: There are many reasons, but probably the most prominent of those is we’re very tightly regulated, and the expectation is that we’re going to have excellent outcomes with every transplant that we do. As a field, we’ve become a little bit more cautious and a little bit more risk-averse, which has resulted in improved outcomes, but fewer numbers of organs getting used.

There have been some misconceptions about which combinations of organs to do. There certainly are some issues with referrals. For the kidney and pancreas patients, we usually capture those at transplant centers that do pancreas transplants when they come in for their kidney, but there are many programs that don’t offer pancreas transplants, or only offer them with very restricted criteria, so those patients might not get captured. Also, the patients who would benefit from getting just a pancreas because of their life-threatening complications, they remain in the diabetologists’ care with optimized medical therapy, which isn’t as good as a pancreas transplant.

Healio:What changes need to be made to increase uptake of pancreas transplantation for people with diabetes?

Fridell: As a medical community, we have to identify the patients that would be suitable candidates for this, think about it at the proper time and refer the patients. We have to educate the patients with diabetes because patients are allowed to refer themselves to transplant hospitals and if they are aware that this is an option — almost all pancreas transplant centers would welcome them. If they aren’t candidates, they can at least have the conversation about what’s involved. Perhaps some of the patients that we see might not be a candidate for pancreas transplant, but once it becomes approved, might be candidates for an islet transplant.

At transplant hospitals, there should be a pathway that when a patient gets referred for a kidney transplant, if they are a good candidate for a pancreas transplant, then there should be a mechanism for either consultation or referral to a sender that does pancreas transplants, so that the patients are informed and could decide which procedure they would like.

References:

  • Fridell JA, et al. J Clin Endocrinol Metab. 2022;doi:10.1210/clinem/dgac644.
  • Stratta RJ, et al. Am J Transplant. 2016;doi:10.1111/ajt.13890.
  • Stratta RJ, et al. Curr Opin Organ Transplant. 2016;doi:10.1097/MOT.0000000000000319.

Racial disparity in kidney transplant survival relates to late rejection and is independent of steroid withdrawal

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Abstract

Black kidney transplant recipients have more acute rejection (AR) and inferior graft survival. We sought to determine whether early steroid withdrawal (ESW) had an impact on AR and death‐censored graft loss (DCGL) in blacks. From 2006 to 2012, AR and graft survival were analyzed in 483 kidney recipients (208 black and 275 non‐black). Rates of ESW were similar between blacks (65%) and non‐blacks (67%). AR was defined as early (≤3 months) or late (>3 months). The impact of black race, early AR, and late AR on death‐censored graft failure was analyzed using univariate and multivariate Cox models. Blacks had greater dialysis vintage, more deceased donor transplants, and less HLA matching, yet rates of early AR were comparable between blacks and non‐blacks. However, black race was a risk factor for late AR (HR: 3.48 (95% CI: 1.87‐6.47)) Blacks had a greater rate of DCGL, partially driven by late AR (HR with late AR: 5.6; 95% CI: 3.3‐9.3). ESW had no significant interaction with black race for risk of early AR, late AR, or DCGL. Independent of ESW, black kidney recipients had a higher rate of late AR after kidney transplantation. Late AR was highly predictive of DCGL and contributed to inferior graft survival in blacks

Retrospective evaluation of the efficacy and safety of belatacept with thymoglobulin induction and maintenance everolimus: A single‐center clinical experience

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Abstract

Belatacept use has been constrained by higher rates of acute rejection. We hypothesized that belatacept with low‐dose rATG and initial mycophenolate maintenance with conversion to everolimus at 1 month post‐transplant ± corticosteroids would improve efficacy and maintain safety. Retrospective single‐center analysis of the first 44 low immunologic risk kidney transplant recipients treated with this regimen. The cohort was 59% male, mean age at transplant of 57 years. Diabetes was the most common cause of ESRD (39%). The mean 1‐year eGFR was 61.4 (SD 18.4) mL/min/1.73 m2. There were five acute cellular rejections (11.4%) that occurred in patients who had changed from everolimus to mycophenolate mofetil due to side effects. Thirty‐two percent developed BK viremia and 12% developed CMV viremia. There were no cases of PTLD. A novel belatacept regimen with rATG induction and maintenance everolimus demonstrated a low acute rejection rate and maintained an excellent 1‐year eGFR.

Outcome of kidney transplant in primary, repeat, and kidney‐after‐nonrenal solid‐organ transplantation: 15‐year analysis of recent UNOS database

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Abstract

The number of nonrenal solid‐organ transplants increased substantially in the last few decades. Many of these patients develop renal failure and receive kidney transplantation. The aim of this study was to evaluate patient and kidney allograft survival in primary, repeat, and kidney‐after‐nonrenal organ transplantation using national data reported to United Network for Organ Sharing (UNOS) from January 2000 through December 2014. Survival time for each patient was stratified into the following: Group A (comparison group)—recipients of primary kidney transplant (178 947 patients), Group B—recipients of repeat kidney transplant (17 819 patients), and Group C—recipients of kidney transplant performed after either a liver, heart, or lung transplant (2365 patients). We compared survivals using log‐rank test. Compared to primary or repeat kidney transplant, patient and renal allograft survival was significantly lower in those with previous nonrenal organ transplant. Renal allograft and patient survival after liver, heart, or lung transplants are comparable. Death was the main cause of graft loss in patients who had prior nonrenal organ transplant.

Post-Transplant LN Patients Can Have Viable Pregnancies

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Outcomes better in women with inactive systemic lupus erythematosus..

Having a renal transplant for lupus nephritis did not rule out successful pregnancies, but outcomes were better in those whose systemic lupus erythematosus (SLE) was inactive, according to an Italian case report.

The researchers, led by Gabriella Moroni, MD, of the Ospedale Maggiore IRCCS, in Milan, analyzed nine pregnancies in three of 38 women who had received kidney transplants at their center. Two patients had received a kidney from a living related donor and one had a received a transplant from a deceased donor.

From 2002 to 2013, five of these post-transplant pregnancies ended in miscarriage. All mothers were in their 30s by the time they conceived, and their initial pregnancies occurred at 4 years, more than 7 years, and almost 9 years after transplantation. In the last case, after two miscarriages, the woman had her first successful pregnancy more than 10 years’ post-transplant at age 38, the group wrote online in Lupus.

Miscarriages in transplanted patients are common, and preconception counseling is essential, the investigators noted.

“Women with stable and prolonged remission of SLE, normal renal function, normal blood pressure, and negative antiphospholipid antibodies (aPL) have good probabilities of positive fetal and maternal outcomes,” they explained.

However, they added that very few cases of post-transplant pregnancy in lupus nephritis (LN) patients have been reported in the literature.

In their study, patients were followed at least once a month and then followed twice weekly from 24 weeks’ gestation onward (including with serial placental Doppler imaging), hospitalized when necessary, and cared for by a multidisciplinary team of gynecologists and nephrologists.

All infants were delivered via cesarean, and the majority were of low birth rate, which may have been partly due to early surgical delivery, the authors explained. However, the infants were healthy and without serious complications, they added.

Immunosuppressive therapy consisted of steroids, calcineurin inhibitors, and mycophenolate mofetil (MMF), which had been replaced with azathioprine before conception. All patients had normal renal function and urinalysis (serum creatinine <1.5 mg/dL) and nonsignificant proteinuria (<500 mg/day). Some signs of immunological activity persisted after transplantation in two patients.

The authors stressed that before pregnancy, patients’ immunosuppressive regimens must be re-evaluated for possible teratogenic effects. They recommended switching from MMF to azathioprine. Also, ACE inhibitors must be discontinued before or at conception, they advised.

They reported that two pregnancies were uneventful. Pre-eclampsia occurred in a hypertensive patient in two pregnancies that ended in preterm delivery in one and newborns of small-for-gestational-age size in both. The authors ascribed these good results partly to the well-planned pregnancies and the specialized intensive care and imaging.

Significantly, although the risk of post-pregnancy graft loss in transplanted mothers is about around 6.9% within the first 5 years of giving birth, graft function continued to be normal in all patients. “To reduce such a risk it is wise to discourage pregnancy within the first year after transplantation,” they wrote. Urinalysis results also remained normal.

The authors noted that recent studies suggest that hydroxychloroquine improves obstetrical outcomes and should be part of immunosuppressive therapy throughout pregnancy.

“It is also important that patients start low-dose aspirin within the first trimester of pregnancy as primary prophylaxis for pre-eclampsia,” they cautioned.

Based on their experience and on published guidelines for renal transplanted patients, Moroni’s group concluded that “pregnancy in patients with kidney transplant due to LN should not be discouraged,” adding that “pre-conception counseling is mandatory.”

Acute Kidney Injury May Not Preclude Transplant

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In light of reasonable 6-month graft function, clinicians should consider kidney transplant from deceased donors with acute kidney injury (AKI), according to a multicenter study published online March 11 in the American Journal of Transplantation. However, there are risks for kidney discard and delayed graft function (DGF), defined as the need for continued dialysis support in the first week after transplantation.

“There appears to be room to attempt more transplants using these AKI kidneys rather than throwing them away,” senior author Chirag R. Parikh, MD, director of the Program of Applied Translational Research at Yale University School of Medicine, New Haven, Connecticut, said in a university news release.

 “The waiting list has grown to over 100,000 patients as thousands more people are wait-listed each year than actually receive a transplant. In addition, the median time it takes for an adult to receive a transplant in the United States increased from 2.7 to 4.2 years between 1998 and 2008, and more than 5,000 people die each year while waiting for a kidney,” Dr Parikh continued.

Using a sample of 1632 donors, Isaac E. Hall, MD, from the Program of Applied Translational Research, Department of Medicine, Yale University School of Medicine, and colleagues examined associations of AKI, defined as increasing admission-to-terminal serum creatinine, with kidney discard, DGF, and 6-month estimated glomerular filtration rate (eGFR).

Compared with donor kidneys with no AKI, kidneys with AKI Network stages 1, 2, and 3 had increased kidney discard risk. Adjusted relative risks were 1.28 (95% confidence interval [CI], 1.08 – 1.52), 1.82 (95% CI, 1.45 – 2.30), and 2.74 (95% CI, 2.00 – 3.75), respectively.

 Donor AKI stage was also linked to risk for DGF, with adjusted relative risks of 1.27 (95% CI, 1.09 – 1.49) for stage 1, 1.70 (95% CI, 1.37 – 2.12) for stage 2, and 2.25 (95% CI, 1.74 – 2.91) for stage 3.

Surprisingly, however, AKI was not linked to poor kidney transplant function 6 months later, and AKI stages did not differ significantly in terms of 6-month eGFR. However, recipients with DGF had significantly lower 6-month eGFR (48 mL/minute per 1.73 m2; interquartile range, 31 – 61 mL/minute per 1.73 m2) than those without DGF (58 mL/minute per 1.73 m2; interquartile range, 45 – 75 mL/minute per 1.73 m2; P < .001).

There was a significant, favorable interaction between donor AKI stage and DGF. Six-month eGFR increased in tandem for DGF kidneys with increasing donor AKI (P for interaction = .05).

“What we saw was, with worsening AKI in the donor, the six-month outcome was actually better for recipients who experienced DGF,” Dr Hall said in the news release.

A possible explanation offered by Dr Hall was that kidneys acutely injured in the donor may develop ischemic preconditioning, which could protect the organs from later injury. Alternatively, the successfully transplanted kidneys with AKI may have been of better quality otherwise than the rejected kidneys with AKI, despite adjustment for donor age, comorbidity, and other clinical factors.

The authors note several study limitations, including its observational design with possible residual confounding and lack of complete follow-up data beyond 6 months. Nonetheless, the study authors suggest considering cautious expansion of the donor pool to deceased donors with AKI.

“Even if it only means a few dozen more kidney transplants each year, those are patients who would come off of the waiting list for transplants sooner and have much better survival than continuing on dialysis in hopes of seemingly higher-quality kidney offers, which may never come in time,” Dr Parikh said in the release.

Some Studies Suggest Antirejection Drugs Not Always Needed to Protect Kidney Graft

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Researchers are exploring the tantalizing prospect of identifying patients with kidney transplants who do not need to continue to take antirejection medicines to preserve their donated organ. At the very least, this line of research might enable physicians to recognize those patients with renal allografts who could take less immunosuppressive medicine, reducing the risks of infection and cancer associated with such drugs.

Figure 05071FA
Researchers are hoping to identify the rare patients with kidney transplants who do not need antirejection medicines, allowing them to avoid the adverse effects of such drugs. (Photo credit: AJPhoto/www.sciencesource.com)

Such hopes were raised by researchers in the United States and Europe who identified biological signatures of a small minority of patients who had stopped taking antirejection medicines for a variety of reasons, such as adverse effects or cost, yet still preserved their allograft function.

source:JAMA