Pancreas-kidney transplantation: A game-changer for diabetic patients with advanced chronic kidney disease and hypoglycemia unawareness

INTRODUCTION AND BACKGROUND

On a global scale, diabetes mellitus (DM) is a key contributor to chronic kidney disease (CKD). It has been estimated that type 2 DM represents 95% of cases, while type 1 represents only about 5% of patients with diabetic kidney disease (DKD). The burden of CKD in the Middle East, including Oman, is remarkable. According to the official statistics, CKD is the eighth leading cause of death in Oman. It is reported that 9.9% of the population in Oman have an estimated glomerular filtration rate (eGFR) below 60 ml/min, and about 1% have an eGFR below 30 ml/min. The incidence and prevalence of CKD in Oman are on the rise, especially in those aged 45 years and older.^[1]

The magnitude of DM as a leading cause of CKD in Oman is even higher than the global average, representing about 46% of all cases of CKD. Epidemiological data showed that the prevalence of DM among the whole population was about 12%, of whom 51% were obese, 46% had proteinuria and/or CKD, and 66% were hypertensive.^[2] Hemodialysis is the Sultanate of Oman’s most widely used form of renal replacement therapy (RRT). Notably, among the hemodialysis population, DKD accounts for more than 50% of all causes of CKD in such patients.

Type 1 DM often affects younger patients and is more frequent in Caucasians. Kidney transplantation (KT) is the best option for a form of RRT when compared to dialysis regarding survival and quality of life. Type 1 DM is often caused by an autoimmune process with the presence of various types of antibodies, such as anti-glutamic acid decarboxylase and anti-islet cell antibodies (ICA), that are directed against specific epitopes of the pancreatic islet cells. On the other hand, the pathogenesis of type 2 DM is insulin resistance with relative insulin deficiency. There is no specific test that accurately differentiates between the two types. The presence of autoantibodies may support the diagnosis of type 1 DM, but their absence does not exclude the diagnosis. In addition, 30% of patients with type 2 DM have positive autoantibodies. Elevated insulin and c-peptide levels support the diagnosis of type 2 DM.^[3]

Hypoglycemia unawareness (HU) can occur in both types, in which the autonomic and neuroglycopenic symptoms of hypoglycemia (e.g., lack of concentration, irritability) decrease and are hardly perceivable. The best treatment option for patients with HU is pancreas transplantation (PT), as will be discussed in this review. PT is an attractive option that can be coupled with KT in patients with advanced CKD. Given the above, it appears logical to consider PT in Oman as a pivotal treatment for HU and those with DKD. The following review will discuss the value and applicability of PT, with a special focus on the combined pancreas and KT in various forms, in addition to islet cell transplantation (ICT).

OVERVIEW OF HU

Symptoms of hypoglycemia often develop when the blood glucose level is less than 3.9 mmol/L. This level is referred to as level 1 hypoglycemia (according to the American Diabetes Association). If blood glucose drops to <3 mmol/L, the patient will likely develop neurological symptoms (level 2 hypoglycemia). Patients with severe hypoglycemia (needing assistance) are classified as having level 3 hypoglycemia.^[4]

Symptoms of hypoglycemia can be classified into two main categories: Autonomic (e.g., palpitation and sweating) and neuroglycopenic (due to glucose deficiency in the brain). Neuroglycopenic symptoms (e.g., drowsiness and confusion) tend to occur at a severe degree of hypoglycemia.^[5]

PATHOPHYSIOLOGY OF HU

1. Autonomic failure: primarily due to suppression of the sympathoadrenal axis.

2. Defective brain sensing of glucose deficiency is due to the deranged mechanism of glucose uptake and signaling and abnormalities of glucose transport.

3. Hormonal dysregulation, including cortisol, glucagon, and epinephrine.

In addition to the above-mentioned proposed mechanisms, CKD and hemodialysis represent an additional risk factor for hypoglycemic events. HU can lead to various adverse clinical outcomes, including but not limited to the risk of falls, injuries, coma, and even cardiac arrest.^[6] Risk factors for HU include CKD, intensive control of blood glucose, heavy exercise, long duration of DM, history of previous hypoglycemic episodes, and alcohol consumption [Figure 1].

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Figure 1:

Risk factors and pathophysiologic mechanisms of hypoglycemia unawareness.

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OPTIONS FOR DIABETIC CONTROL IN PATIENTS WITH HU AND ADVANCED CKD

The best option for diabetic control for patients with HU would be PT. Simultaneous pancreas-kidney (SPK) transplants, pancreas after kidney (PAK), or kidney transplant alone are possible options for patients having advanced CKD approaching end-stage renal disease (ESRD). Furthermore, pancreatic ICT is another option if coupled with KT (discussed below in more detail). Pancreas transplant alone (PTA) is not suitable for patients with eGFR <20 mL/min.

In this respect, PT offers an euglycemic state, leading to a better quality of life and offering the patient the potential to be free from exogenous insulin doses. Furthermore, PT may retard the progression of micro and macrovascular complications and diabetic neuropathy. The PT success rate has increased in the modern era due to the advances in immunosuppressive medications and better surgical techniques.^[7,8] In some reports, the 1-year pancreas graft survival was about 95% in SPK compared to 86% in those with PAK.^[9]

CHOOSING THE BEST OPTION

Patient and graft survival and post-operative complications are the main points of concern when choosing the appropriate approach and the “best option.” Deceased donor kidney transplant (DDKT) has been associated with much worse outcomes compared to living donor kidney transplant (LDKT). Therefore, it is sometimes logical to consider LDKT as long as potential donors are available. The patient would then be listed for PAK, which can be performed after a period of clinical stability. If SPK is considered, this carries the drawback of continuing on regular dialysis for a longer time, as long as the patient is listed on SPK. However, patients with a GFR of 20 mL/min or more may have some privileges if listed early for SPK and do not need to start regular dialysis at this level.

In a study by Knoll and Nichol, patients with ESRD and type 1 DM were evaluated for various options. LDKT individuals had the best long-term life expectancy and quality of life. The following best outcome was achieved in SPK and PAK. DDKT had the worst outcome of all. When the investigators excluded LDKT from the analysis, SPK had a better life expectancy than PAK. The relative risk for death for PTA and PAK was 1.57 and 1.42, respectively, after 4 years of follow-up. SPK had a 60% reduction in mortality compared to patients on the waiting list.^[10]

The outcome of PT has shown consistent improvement over time regarding patient and graft survival.^[11] Gruessner and Gruessner^[12] analyzed the data from the International Pancreas Transplant Registry and recorded and evaluated the 5-, 10-, and 20-year pancreatic graft survival [Table 1].

According to the registry report in 2022, patient survival after SPK has improved significantly over time. Patient survival at 1 year has reached 97.6%, while 10-year survival has been 71.6%. PAK patient survival was 64.8% at 10 years. On the other hand, PTA patient survival at 10 years has been 72.3%.^[12]

It is worth noting that PAK may provide better renal graft survival in diabetic patients compared to KT patients without a PT. In addition, a patient having a living donor kidney graft in PAK decreased the relative risk of mortality, while having a deceased donor kidney raised the relative risk by 46%.^[13]

Interestingly, it has been reported that recurrent DKD has rarely recurred in functioning SPK transplants.^[14] Regarding mortality, cardiovascular (CV) disease represents the leading cause of death in all types of PT. The most important risk factors are:

1. Renal graft loss.

2. Loss of pancreas graft due to either technical or immunological factors.

3. Age more than 45 years.

4. DM more than 25 years.

Some studies showed no difference in patient survival between SPK and PAK. Others have shown better graft survival in LDKT when compared to SPK; however, the patient survival was similar.^[15] Another study by Kamgar et al. compared the graft and patient survival in zero human leukocyte antigen (HLA) mismatched patients to LDKT and SPK.^[16] There were no significant differences between all groups regarding patient and graft survival, reflecting that if the waiting time for SPK is expected to be too long, then it would be wiser to proceed to a zero HLA-mismatched DDKT, if available.

On the other hand, other long-term studies have shown better patient survival in SPK compared to LDKT or PAK approaches due to a proposed benefit of a functioning pancreas since the first moment of KT, thus reducing the CV risk, which is the leading cause of mortality among patients with CKD.^[17-19] Pre-dialysis SPK has shown clear advantages over post-dialysis SPK in various studies, including patient and graft survival.^[20]

COMPLICATIONS OF PT

• Vascular thrombosis can occur in the 1^st–2^nd postoperative days, possibly due to reperfusion pancreatitis and the relatively low blood flow to the pancreas. To minimize this risk, proper donor selection, appropriate surgical procedures, and short cold ischemia time should be implemented.^[21]

• Transplantation pancreatitis: Mild pancreatitis is common postoperatively, evident by elevation of lipase and amylase. Fortunately, most cases are transient.

• Complications of enteric-drained PT: Leaks and intra-abdominal abscesses are the most feared complications. These can happen 1-6 months after PT. The patient may complain of fever and abdominal pain. A CT scan can help establish the diagnosis. Gastrointestinal (GI) bleeding is another complication that is often mild but may need operative exploration in some cases.

• Complications of bladder-drained PT: Urine and exocrine pancreatic secretion leaks can occur from the duodenal segment’s breakdown. Exploration is usually required for repair. Other complications include hematuria, urinary tract infections, stone formation, reflux pancreatitis, and metabolic acidosis.

• Rejection: There is a 10–20% risk of graft rejection during the 1^st post-operative year. Rejection may be cell or antibody-mediated.^[22] Risk factors include advanced donor age, PTA, non-primary SPK, and race mismatch.

• Pancreatic failure means the resumption of anti-diabetic medications that are close to or more than those used before PT. Elevated glycosylated hemoglobin and the absence of measured C-peptide are remarkable findings.

THE PRE-TRANSPLANT WORKUP

The pre-transplant workup needs a multidisciplinary team approach, including physicians, transplant surgeons, psychologists, nurses, dieticians, pharmacists, radiologists, and laboratory and social care specialists. The transplant team should exclude the absolute and relative contraindications for PT [Table 2].

CHOICE OF THE IMMUNOSUPPRESSIVE PROTOCOL

Most protocols are similar to that of KT alone. However, the incidence of rejection is higher in KT alone (17% for SPK, 20% for PAK, and 24% for PTA after 1 year), which is almost twice the rejection rate in KT alone. Induction therapy options include anti-CD52 alemtuzumab and antithymocyte globulin. The interleukin two blockers are not widely used in PT. Maintenance therapy includes triple agents, mycophenolate, steroids, and a calcineurin inhibitor (CNI), either tacrolimus or cyclosporine. Steroid withdrawal or avoidance approaches are becoming more popular than before in many centers.^[23]

Tacrolimus is generally preferred to cyclosporine. The target tacrolimus trough level is 8–12 ng/mL during the early post-transplant period and 6–8 ng/mL thereafter. Drug interactions with CNIs should always be considered.

Long-term use of CNI may be associated with nephrotoxicity and beta cell derangement.^[24] Hence, there is a trend to minimize CNI use in PT, which is advocated in some protocols. The costimulatory blocker, belatacept, has been considered in such cases.^[25] The use of belatacept has not been linked to nephrotoxicity, beta cell injury, or glucose intolerance. Switching from CNI to belatacept is an option that should be considered if feasible. The use of mammalian target of rapamycin inhibitors (mTOR inhibitors) has been used with promising results regarding patient and graft survival.^[26]

Steroid use is well known to be associated with glucose intolerance, hyperglycemia, and new-onset diabetes after transplantation. Furthermore, obesity, hypertension, dyslipidemia, and other steroid side effects represent a challenge for transplant recipients. Steroid withdrawal or avoidance protocols have been points of debate in such situations, with somewhat conflicting results between studies. Some studies implemented steroid avoidance with successful outcomes. However, long-term outcomes have not yet been validated.^[27]

Prophylaxis against infection includes valganciclovir for CMV, oral antifungal gel preparations, and antibiotic prophylaxis against urinary infections. When indicated, screening for polyomavirus with urine cytology and serum polymerase chain reaction is also recommended.

FOLLOW-UP PLAN AFTER TRANSPLANTATION

Follow-up of the patient with pancreas and kidney grafts aims to detect any possible rejection, immunosuppression complications, and other possible complications. A proposed follow-up schedule would be as follows:

• Post-operative weeks 1–2: twice weekly.

• Week 3–4: Once weekly.

• Then, one visit on a monthly basis in the first 6 months.

• During the rest of the first year, every 3 months.

• During the second year, every 6 months.

• If the patient is stable, one visit on an annual basis can be considered thereafter.

• The patient should be instructed to contact the transplant team once any unusual complaint is experienced (e.g., fever, decline in urine output, or abdominal pain).

ICT, AN ATTRACTIVE, LESS INVASIVE OPTION

Early trials of ICT were not satisfactory. However, in 2000, Shapiro et al. reported successful outcomes in 7 patients with type 1 DM, despite some safety concerns.^[28] Since then, the outcome of ICT has been improving and is currently considered an attractive option for managing DM, especially for type 1 DM and those with HU.

The classical ICT process involves isolating and purifying islet cells from a donor pancreas (allogenic or xenogeneic), followed by infusion into the recipient portal vein. The concept of islet transplantation is to establish intrinsic glucose-responsive insulin-secreting mechanisms versus the conventional fixed insulin regimens. This may resemble the physiological insulin secretion and offers a better quality of glucose control, with a considerable potential for reducing diabetic complications and delivering a better quality of life.^[29]

Complications of traditional ICT (through the portal vein) include post-transplant inflammatory response and rejection, which may lead to islet necrosis or dysfunction. Portal vein thrombosis and portal hypertension have also been encountered.^[30] In 2006, the “Edmonton protocol” was implemented, with a considerably favorable outcome in type 1 DM. Promoting this protocol led to further improvements in ICT, with a stabilized insulin level, glycemic control, and minimizing HU. This is considered an important milestone in such a therapeutic approach.^[31]

Unlike the portal vein, the omentum is regarded as a potentially important transplantation site. It is highly vascular and contains valuable growth factors such as vascular endothelial growth factor and stromal cell-derived factor 1. Such factors enhance islet cell survival and vascularization.^[32]

The subcutaneous space is another potential transplant site. Yu et al. reported subcutaneous islet transplant in animal models, with a successful outcome regarding glycemic control. In addition, the procedure was safe and relatively simple.^[33]

Various anti-inflammatory drugs have been used to reduce the inflammatory response following ICT, including interleukin 1 receptor antagonists and tumor necrosis alpha inhibitors.^[34] Alpha 1 anti-trypsin is another promising serine pinhibits cytokine release and preventsrotease inhibitor that inhibited cytokine release and prevented islet cell apoptosis in animal models.^[35]

CONCLUSION

Pancreas-KT is regarded as a transformative option for diabetic patients with advanced CKD and HU. This clinical approach addresses the burden of CKD and offers better glycemic control, glucose-responsive insulin production, favorable long-term outcomes, and better quality of life. The advancements in surgical techniques, newer immunosuppressive regimens (including belatacept and mTOR inhibitors), and a perfectly designed post-operative follow-up plan have led to much better clinical outcomes.

Long-term studies have shown better patient survival in SPK compared to LDKT or PAK approaches. This is due to the proposed benefit of a functioning pancreas since the first moment of KT, thus reducing the CV risk. In some reports, the one-year pancreas graft survival was about 95% in SPK compared to 86% in those with the PAK approach.

Another promising approach in the management of HU is ICT – a less invasive approach with favorable outcomes. Traditional ICT through the portal vein has been associated with some troublesome complications. However, ongoing research involving alternative sites, including the omentum and subcutaneous space, holds a promising future for refined ICTs with favorable outcomes and better safety profiles.

To conclude, PT is pivotal in the management of patients with HU, which can be coupled with KT for patients with advanced CKD and DM. A multidisciplinary team approach would be essential to implement this approach in Oman, as DKD is a substantial cause of CKD, resulting in a significant health burden. This would represent a new era in the management of DM and CKD, with the hope of improving survival and quality of life in such patients.