Pancreas Kidney Transplantation
Number: 0587
Table Of Contents
PolicyApplicable CPT / HCPCS / ICD-10 Codes
Background
References
Policy
Scope of Policy
This Clinical Policy Bulletin addresses pancreas kidney transplantation.
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Medical Necessity
Simultaneous Pancreas-Kidney (SPK) and Pancreas and Living-Donor Kidney (SPLK) Transplantation
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Aetna considers simultaneous pancreas-kidney (SPK) transplantation and simultaneous cadaver-donor pancreas and living-donor kidney (SPLK) transplantation medically necessary for members with diabetes and end-stage renal disease (ESRD) who meet the transplanting institution's selection criteria. In the absence of an institution's selection criteria, Aetna considers SPK transplantation and SPLK transplantation medically necessary in persons with diabetes and ESRD when all of the following selection criteria are met, and none of the following absolute contraindications is present:
- Member has a creatinine clearance (Clcr), calculated by the Cockcroft-Gault formula (see Appendix), of less than 20 ml/min, or a directly measured glomerular filtration rate (GFR) of less than 20 ml/min; and
- Member has ESRD and requires dialysis or is expected to require dialysis in the next 12 months.
Aetna considers SPK and SPLK transplantation not medically necessary for persons with poorly controlled HIV infection. HIV infection is considered poorly controlled if any of the following is present:
- HIV-1 RNA (viral load) is not at undetectable levels; or
- Member has not been on stable anti-viral therapy for at least 3 months; or
- Member has opportunistic infections or neoplasms; or
- Member's CD4 count has not been 200 cells/mm3 or greater for at least 6 months.
- Because of the success of protease inhibitors, the literature indicates the HIV-positive person may be a candidate for transplant if the CD4 count is more than 200 cells/mm3 for greater than 6 months, on stable anti-viral therapy more than 3 months, no opportunistic infections or neoplasms, and viral load is undetectable.
- Aetna considers SPK and SPLK transplantation medically necessary for persons with any of the following relative contraindications if the attending physician determines and documents that the potential benefits of SPK or SPLK transplantation outweigh the risks. Relative contraindications to SPK and SPLK transplantation include:
- Chronic liver disease;
- Clinical evidence of severe cerebrovascular or peripheral vascular disease (e.g., ischemic ulcers, previous amputation secondary to severe peripheral vascular disease, severe iliac disease, blindness). Adequate peripheral arterial supply should be determined by standard evaluation in the vascular laboratory including Doppler examination and plethysmographic readings of systolic blood pressure;
- No uncontrolled and/or untreated psychiatric disorders that interfere with compliance to a strict treatment regimen (exception to this contraindication will be allowed with supporting documentation (within 4 weeks) demonstrating 3 months of stability from treating addiction medical professional or psychiatrist);
- Persons with body mass index (BMI) of 35 or higher and type 2 diabetes (bariatric surgery should be considered);
- Structural genito-urinary abnormality or recurrent urinary tract infection;
- Treated malignancy (SPK or SPLK transplantation is considered medically necessary in persons with malignant neoplasm if the neoplasm has been adequately treated and the risk of recurrence is small);
- Uncontrolled hypertension.
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Contraindications
Aetna considerrs SPK and SPLK transplantation not medically necessary for members with any of the following absolute contraindications:
- Inability to adhere to the regimen necessary to preserve the transplant
- Malignant neoplasm (other than non-melanomatous skin cancer or low grade prostate cancer) that has a significant risk of recurrence
- Ongoing or recurrent active infections that are not adequately treated
- Persistent substance abuse
- Severe uncorrectable cardiac disease (e.g., coronary angiographic evidence of significant non-correctable coronary artery disease, refractory congestive heart failure, ejection fraction below 40%, myocardial infarction less than 3 months ago) (cardiac status should be re-evaluated annually while on waiting list)
- Unresolvable current psychosocial problems.
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Experimental and Investigational
The following procedures are considered experimental and investigational because the effectiveness has not been established:
- Georges Lopez Institute preservation solution (IGL-1) for pancreas-kidney (SPK) transplantation. Note: The preservation solution would be considered integral to the transplant surgery and not separately reimbursed.
- Measurement of donor-derived cell-free DNA of transplant recipients for monitoring of rejection.
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Related Policies
- CPB 0493 - Kidney Transplantation - for isolated kidney transplant
- CPB 0601 - Pancreas Transplantation Alone (PTA) and Islet Cell Transplantation - for pancreas after kidney (PAK) transplant
Background
Diabetes mellitus is the most common endocrine disease worldwide and is the leading chronic disease in children. Despite the success of exogenous insulin therapy, numerous long-term sequelae develop in patients with diabetes, including end-stage renal failure, cardiovascular disease, autonomic and somatic neuropathy, and blindness. Chronically abnormal lipid metabolism, accelerated atherosclerosis, and destruction of the microvascular system result in global vascular disease, leading to amputations and premature death from myocardial infarctions and cerebrovascular accidents. Occurring in approximately 1 % of the population, diabetes accounts for more than 160,000 deaths annually in the United States. According to the United States End-Stage Renal Disease (ESRD) Registry, diabetic patients between the ages of 20 and 45 who have to undergo dialysis as their only treatment option have less than 20 % survival after 10 years. Solitary renal transplantation with continued administration of exogenous insulin for glucose control is a good option for diabetic recipients as it has 5-year survival rates approaching 70 % for cadaveric renal transplants and 85 % for living related donor (LRD) transplants; however, the diabetic state remains associated with poor patient survival.
Reported in 1993, the Diabetes Control and Complications Trial Study conclusively showed that tight glucose control significantly decreases nephropathy, retinopathy, and neuropathy in patients with type 1 diabetes, and this provided the impetus for combining pancreas transplantation with kidney transplantation. In selected patients and without compromising survival rates, both diabetes and ESRD can be eliminated by simultaneous pancreas and cadaver kidney (SPK) transplantation and LRD kidney transplantation alone followed by a solitary cadaver-donor pancreas transplant (sequential pancreas after kidney [PAK] transplantation). SPK transplantation is more widely used than PAK, because SPK is a single operation and there is an "immunologic advantage" for the pancreas because the kidney can serve as a reliable marker for rejection of the pancreas. However, some advocate PAK transplantation if there is a willing LRD. Use of a well-matched living-donor kidney offers the potential benefits of shorter waiting time, expansion of the organ donor pool, and improved short-term and long-term renal graft function. SPK pancreas graft survival has historically exceeded that of solitary pancreas transplantation; however, recent improvements in solitary pancreas transplant survival rates have narrowed the advantage seen with SPK. Both SPK and PAK impose greater immunologic risks over kidney transplant alone.
- quality of life is improved since it usually removes dependence on both insulin and dialysis;
- recurrence of diabetic nephropathy is attenuated;
- diabetic retinopathy is reduced;
- progression of diabetic neuropathy may be halted and in some cases reversed, including improvements in autonomic neuropathy, enhancing both cardiac reflex function and gastric motility in some cases; and
- beneficially affects patient survival even though this glycemic control is given as a late intervention in a diabetic patient's lifetime.
The American Diabetes Association (2003) has concluded that pancreas-kidney transplantation is indicated in patients with insulin-dependent diabetes and end stage renal disease: “Pancreas transplantation should be considered an acceptable therapeutic alternative to continued insulin therapy in diabetic patients with imminent or established end-stage renal disease who have had or plan to have a kidney transplant, because the successful addition of a pancreas does not jeopardize patient survival, may improve kidney survival, and will restore normal glycemia.”
An assessment by the Institute for Clinical Systems Improvement (ICSI, 2003) stated that “[n]early all uremic diabetics are candidates for a kidney transplant and most should also receive a pancreas either simultaneously (SPK) or sequentially (PAK). For those who have a living donor for a kidney, PAK is preferable to waiting years for a cadaver SPK". The ICSI assessments notes that experience with pancreas transplant for type 2 diabetes is more limited than for type 1 diabetes. The assessment reports that approximately 6 % of pancreas transplants are done in patients with type 2 diabetes and about 94 % are done in patients with type 1 diabetes. The ICSI guideline describes an unpublished study by Elkhammas et al (1999) of SPK transplantation in 299 patients with type 2 diabetes who received pancreas transplants from 1994 to 1999. The study noted that, at 5 years, 86 % of patients survived, 73 % of pancreas grafts survived, and 75 % of kidney grafts survived.
Nath et al (2005) reported on the results of pancreas transplant in 17 patients with type 2 diabetes transplanted between 1994 through 2002. Of the 17 transplants, 7 (41 %) were a SPK, 4 (24 %) were a PAK, and 6 (35 %) were a pancreas transplantation alone (PTA). One recipient died during the peri-operative period because of aspiration. The other 16 recipients became euglycemic post-transplant and had a functional graft at 1 year post-transplant. After a mean follow-up of 4.3 years post-transplant, the patient survival rate is 71 % (12 of 17). The investigators reported that the 4 additional deaths were due to sepsis (n = 2), suicide (n = 1), and unknown cause (n = 1). The investigators noted that all 4 of these recipients were insulin-independent at the time of death, although 1 was on an oral hypoglycemic agent. The investigators reported that, of the 12 recipients currently alive, 11 remain euglycemic without requiring insulin therapy or oral hypoglycemic agents, and 1 recipient began insulin therapy 1.2 years post-transplant.
Light and Barhyte (2005) reported on 10- to 15-year results of SPK transplants in 135 type 1 and type 2 patients who were dependent on insulin. Twenty-eight percent of the patients in the cohort had type 2 diabetes. The investigators reported that, at 5 and 10 years, pancreas survival for type 1 diabetes was 71 % and 49 %; for type 2 diabetes it was 67 % and 56 % (p = 0.52). Kidney survival at 5 and 10 years for patients with type 1 diabetes was 77 % and 50 %; for patients with type 2 diabetes, it was 72 % and 56 % (p = 0.65). Patient survival at 5 and 10 years with 85 % and 63 % for patients with type 1 diabetes mellitus, and was 73 % and 70 % for patients with type 2 diabetes (p = 0.98). The investigators concluded that the outcomes of SPK transplants are equivalent regardless of diabetes type.
The pros and cons of SPK and PAK must be weighed in each individual patient to determine proper treatment. The graft survival rate of living related kidney allografts significantly exceed that of cadaveric renal transplants because they have less immunologic disparity and comparatively minimal preservation injury. However, in the setting of diabetes, with the possibility of recurrent diabetic nephropathy and other disabling complications, the medical literature indicates that the addition of a pancreas transplant might provide benefits that outweigh the advantages of LRD renal transplantation. SPK transplantation is associated with excess initial morbidity and an uncertain effect on patient survival when compared with solitary cadaveric or living donor renal transplantation. Recent studies show rejection rates after SPK transplantation have now diminished to less than 5 % within the first 6 months. The results also show that SPK has long-term transplant survival rates, which are equal to or even better than survival rates of kidneys from the very best matched live donors. Certainly, survival of SPK transplants is superior to cadaver kidney transplants alone in the diabetic population.
Largely because of these results, and because of the distinct advantages of living kidney donation, some centers have developed a new approach for uremic diabetic patients: simultaneous cadaver-donor pancreas and living-donor kidney transplantation (SPLK). As a single procedure, SPLK has obvious advantages over the standard living-donor kidney transplant followed by PAK. Moreover, because the SPLK kidney is from a living donor, there may be both short-term and long-term benefits over SPK transplantation. Potential benefits of SPLK for diabetic uremic patients include a shorter waiting time for transplantation and better early and long-term renal graft function. Generalized use of SPLK transplantation would expand the renal organ donor pool, thus benefiting all patients waiting for a kidney transplant. The main drawback to SPLK -- coordination of a living donor nephrectomy with a cadaver pancreas transplant -- is easily overcome.
With improved surgical technique and better organ preservation, the remaining obstacle was a high rejection rate of both the kidney and the pancreas. However, with the introduction of more immunosuppressant alternatives, rejection rates have now been reduced. The addition of mycophenolate mofetil (CellCept) and tacrolimus (Prograf) have been extremely helpful options in the immunosuppressive management. Furthermore, induction protocols utilizing basiliximab (Simulect) or daclizumab (Zenapax) are less complicated and have been shown to be better tolerated than the previous induction protocols with anti-lymphocyte globulin (ALG) or OKT3 (Muromonab-CD3). The reported 1-year pancreas graft survival rate for SPK transplantation is now 83 %. The results of PAK have lagged behind the excellent results of SPK transplantation. During the past 3 to 4 years, the reported 1-year pancreas graft survival rate for PAK recipients has improved from 54 % survival to 71 %, shrinking the "immunologic advantage" of combining a cadaver pancreas with a kidney from the same donor.
Members referred for SPK transplantation, who are acceptable candidates by all criteria, should be counseled about possible living donor kidney transplantation. Since there is an extreme shortage of cadaver kidneys in the United States and because living donor kidneys have a survival advantage over cadaver kidneys, generally accepted guidelines state that persons with diabetes with ESRD referred for SPK transplantation should consider living donor kidney transplant alone (LDKTA) followed by a pancreas after kidney (PAK) procedure. Studies show that the LDKTA and PAK option carries equal pancreatic transplant success as SPK transplantation combined with the added survival advantage of LDKTA.
Margreiter et al (2013) systematically reviewed the relevant literature with regard to various biomarkers, imaging techniques, and pathologic evaluation of allograft tissue following pancreas transplantation. More recent studies including graft histology demonstrated the low specificity of pancreatic enzymes as a marker of acute rejection. On the other hand, most blood and serum markers are indicative of an activated immune status rather than rejection. Interestingly, the concomitantly transplanted kidney from the same donor does not seem to be a reliable surrogate marker. Although computed tomography or ultrasound-guided percutaneous biopsies of the pancreas are performed more frequently at present, the complication rate is still as high as 11 %. In contrast, cystoscopic and enteroscopic biopsies of the duodenal part of the graft are associated with almost no complications. The few clinical studies dealing with the duodenum as surrogate marker for the pancreas report a high correlation between duodenum mucosal and pancreas parenchymal histology. The authors concluded that pancreatic graft parenchymal biopsy remains the gold standard in diagnosing pancreatic rejection, as clinical parameters, pancreatic enzymes, non-invasive biomarkers, and surrogate renal biopsies are not reliable tools. Endoscopically obtained duodenal cuff biopsies are a less invasive alternative to percutaneous biopsies.
Kobayashi et al (2014) studied and compared clinical and functional outcomes after simultaneous deceased donor pancreas and kidney transplantation (SPK DD), simultaneous deceased donor pancreas and living donor kidney transplantation (SPK DL), and simultaneous living donor pancreas and kidney transplantation (SPK LL). From January 1, 1996 to September 1, 2005, a total of 8,918 primary SPK procedures were reported to the International Pancreas Transplant Registry. Of these, 8,764 (98.3 %) were SPK DD, 115 (1.3 %) were SPK DL, and 39 (0.4 %) were SPK LL. These researchers compared these 3 groups with regard to several end-points including patient and pancreas and kidney graft survival rates. The 1-year and 3-year patient survival rates for SPK DD were 95 % and 90 %, 97 % and 95 % for SPK DL, and 100 % and 100 % for SPK LL recipients, respectively (p ≥ 0.07). The 1-year and 3-year pancreas graft survival rates for SPK DD were 84 % and 77 %, 83 % and 71 % for SPK DL, and 90 % and 84 % for SPK LL recipients, respectively (p ≥ 0.16). The 1-year and 3-year kidney graft survival rates for SPK DD were 92 % and 84 %, 94 % and 86 % for SPK DL, and 100 % and 89 % for SPK LL recipients, respectively (p ≥ 0.37). The authors concluded that patient survival rates and graft survival rates for pancreas and kidney were similar among the 3 groups evaluated in this study.
In a Cochrane review, Montero et al (2014) noted that pancreas or kidney-pancreas transplantation improves survival and quality of life for people with type 1 diabetes mellitus and kidney failure. Immunosuppression after transplantation is associated with complications. Steroids have adverse effects on cardiovascular risk factors such as hypertension, hyperglycemia or hyperlipidemia, increase risk of infection, obesity, cataracts, myopathy, bone metabolism alterations, dermatologic problems and Cushingoid appearance; whether avoiding steroids changes outcomes is unclear. These investigators evaluated the safety and effectiveness of steroid early withdrawal (treatment for less than 14 days after transplantation), late withdrawal (after 14 days after transplantation) or steroid avoidance in patients receiving PTA, SPK or PAK. They searched the Cochrane Renal Group's Specialised Register (to June 18, 2014) through contact with the Trials' Search Co-ordinator. They hand-searched: reference lists of nephrology textbooks, relevant studies, recent publications and clinical practice guidelines; abstracts from international transplantation society scientific meetings; and sent emails and letters seeking information about unpublished or incomplete studies to known investigators. These researchers included randomized controlled trials (RCTs) or cohort studies of steroid avoidance (including early withdrawal) versus steroid maintenance or versus late withdrawal in pancreas or pancreas with kidney transplant recipients. They defined steroid avoidance as complete avoidance of steroid immunosuppression, early steroid withdrawal as steroid treatment for less than 14 days after transplantation and late withdrawal as steroid withdrawal after 14 days after transplantation. Two authors independently assessed the retrieved titles and abstracts, and where necessary the full text reports to determine which studies satisfied the inclusion criteria. Authors of included studies were contacted to obtain missing information. Statistical analyses were performed using random effects models and results expressed as risk ratio (RR) or mean difference (MD) with 95 % confidence interval (CI). Cohort studies were not meta-analyzed, but their findings summarized descriptively. A total of 3 RCTs enrolling 144 participants met the inclusion criteria: 2 compared steroid avoidance versus late steroid withdrawal and 1 compared late steroid withdrawal versus steroid maintenance. All studies included SPK and only 1 also included PTA. All studies had an overall moderate risk of bias and presented only short-term results (6 to 12 months). Two studies (89 participants) compared steroid avoidance or early steroid withdrawal versus late steroid withdrawal. There was no clear evidence of an impact on mortality (2 studies, 89 participants: RR 1.64, 95 % CI: 0.21 to 12.75), risk of kidney loss censored for death (2 studies, 89 participants: RR 0.35, 95 % CI: 0.04 to 3.09), risk of pancreas loss censored for death (2 studies, 89 participants: RR 1.05, 95 % CI: 0.36 to 3.04), or acute kidney rejection (1 study, 49 participants: RR 2.08, 95 % CI: 0.20 to 21.50), however results were uncertain and consistent with no difference or important benefit or harm of steroid avoidance/early steroid withdrawal. The study that compared late steroid withdrawal versus steroid maintenance observed no deaths, no graft loss or acute kidney rejection at 6 months in either group and reported uncertain effects on acute pancreas rejection (RR 0.88, 95 % CI: 0.06 to 13.35). Of the possible adverse effects only infection was reported by 1 study. There were significantly more UTIs reported in the late withdrawal group compared to the steroid avoidance group (1 study, 25 patients: RR 0.41, 95 % CI: 0.26 to 0.66). These researchers also identified 13 cohort studies and 1 RCT that randomized tacrolimus versus cyclosporine. These studies in general showed that steroid-sparing and withdrawal strategies had benefits in lowering HbAc1 and risk of infections (BK virus and cytomegalovirus [CMV] disease) and improved blood pressure control without increasing the risk of rejection. However, 2 studies found an increased incidence of acute pancreas rejection (HR 2.8, 95 % CI: 0.89 to 8.81, p = 0.066 in 1 study and 43.3 % in the steroid withdrawal group versus 9.3 % in the steroid maintenance, p < 0.05 at 3 years in the other) and 1 study found an increased incidence of acute kidney rejection (18.7 % in the steroid withdrawal group versus 2.8 % in the steroid maintenance, p < 0.05) at 3 years. The authors concluded that there is currently insufficient evidence for the benefits and harms of steroid withdrawal in pancreas transplantation in the 3 RCTs (144 patients) identified. The results showed uncertain results for short-term risk of rejection, mortality, or graft survival in steroid-sparing strategies in a very small number of patients over a short period of follow-up. Overall the data was sparse, so no firm conclusions are possible. Moreover, the 13 observational studies findings generally concur with the evidence found in the RCTs.
Gruessner and colleagues (2017) stated that pancreas transplantation remains the best long-term treatment option to achieve euglycemia and freedom from insulin in patients with labile diabetes mellitus. It is an approved procedure for type 1 diabetes mellitus (T1DM), but it is still considered controversial for type 2 diabetes mellitus (T2DM). These investigators analyzed all primary deceased donor pancreas transplants in patients with T2DM reported to IPTR/UNOS between 1995 and 2015. Characteristics, outcomes, and risk factors over time were determined using uni-variate and multi-variate methods. The focus was on SPK transplants, the most common pancreas transplant category. Patient, pancreas, and kidney graft survival rates increased significantly over time and reached 95.8, 83.3, and 91.1 %, respectively, at 3 years post-transplant for transplants performed between 2009 and 2015. The authors concluded that SPK is a safe procedure with excellent pancreas and kidney graft outcome in patients with T2DM. The procedure restored euglycemia and freedom from insulin and dialysis. They stated that based on these findings, SPK should be offered to more uremic patients with labile T2DM.
Measurement of Donor-Specific Cell-Free DNA for Monitoring Transplant Recipients for Rejection
Knight and colleagues (2019) noted that there is increasing interest in the use of non-invasive biomarkers to reduce the risks posed by invasive biopsy for monitoring of solid organ transplants (SOTs). One such promising marker is the presence of donor-derived cell-free DNA (dd-cfDNA) in the urine or blood of transplant recipients. These investigators systematically reviewed the published literature investigating the use of cfDNA in monitoring of graft health following SOT. Electronic databases were searched for studies relating cfDNA fraction or levels to clinical outcomes, and data including measures of diagnostic test accuracy were extracted. Narrative analysis was performed. A total of 95 articles from 47 studies met the inclusion criteria (18 kidneys, 7 livers, 11 hearts, 1 kidney-pancreas, 5 lungs, and 5 multi-organs). The majority were retrospective and prospective cohort studies, with 19 reporting diagnostic test accuracy data. Multiple techniques for measuring dd-cfDNA were reported, including many not requiring a donor sample; dd-cfDNA fell rapidly within 2 weeks, with baseline levels varying by organ type. Levels were elevated in the presence of allograft injury, including acute rejection and infection, and return to baseline following successful treatment. Elevation of cfDNA levels was observed in advance of clinically apparent organ injury. Discriminatory power was greatest for higher grades of T cell-mediated and acute antibody-mediated rejection (AMR), with high negative predictive values (NPVs). The authors concluded that cell-free DNA is a promising biomarker for monitoring the health of SOTs. These researchers stated that future studies will need to define how it can be used in routine clinical practice and determine clinical benefit with routine prospective monitoring.
Williams et al (2022a) noted that allograft biopsy is the gold standard for diagnosing graft rejection following SPK transplant (SPKTx). Intraperitoneal biopsies are technically challenging and can be burdensome to patients and the healthcare system. Donor-derived cell-free DNA (dd-cfDNA) is well-studied in kidney transplant recipients; however, it has not yet been studied in the SPK population. These researchers hypothesized that dd-cfDNA could be employed for rejection surveillance following SPKTx. They prospectively collected dd-cfDNA in 46 SPKTx patients at a single institution. There were 10 rejection events, 5 of which were confirmed with biopsy. The other 5 were treated based on dd-cfDNA and clinical data alone with favorable outcomes. Among all patients who did not have rejection, 97 % had dd-cfDNA of less than 0.5 %. dd-cfDNA may also help differentiate rejection from graft injury (i.e., pancreatitis) with median values in rejection 2.25 %, injury 0.36 %, and quiescence 0.18 % (p = 0.0006). The authors concluded that similar to kidneys, dd-cfDNA shows promise for rejection surveillance in SPKTx recipients. Moreover, these investigators stated that there is much more work to be carried out; additional studies should be pursued, especially multi-center collaborations, which would increase sample sizes and statistical power of this relatively small cohort of patients worldwide.
The authors stated that drawbacks of this study included inconsistent collection of some important variables, such BK virus or donor-specific antibodies (DSA), which precluded additional conclusions and should be studied in the future. Another major drawback was sample size. Although 46 patients could be considered a large cohort in the SPK population, the number of biopsy-confirmed rejection events was perhaps too small to draw more meaningful conclusions. The methods used to diagnose rejection were not perfectly consistent and should be considered a drawback as well. The most obvious inconsistency was that some patients were diagnosed with a biopsy, whereas others were diagnosed clinically. The authors would have preferred every diagnosis of rejection to be confirmed by allograft pancreas biopsy; however, this was not always feasible. In some cases, the best interest of individual patients (on anticoagulants for example) took priority over the research protocol. In other patients, biopsies were attempted but could not be completed because of the lack of a safe window for CT-guided biopsy. Even in those who were able to undergo biopsy, the findings were not always consistent with clinical impression, and the clinical judgment took precedence. As previously mentioned, the authors’ practice changed from duodenal biopsy to pancreas biopsy during the study period. Furthermore, pathologic analysis of allograft pancreas biopsies has significant room for improvement. As an example, 1 patient was diagnosed as acute cellular rejection (ACR) in the pancreas; however, weeks later, his diagnosis was changed to a mixed rejection after C4d tests returned positive. Thus, although their difficulty in obtaining pancreas biopsies should be viewed as a limitation, it also illustrated the challenges with biopsy of the pancreas allograft, which should be the focus of future research and quality improvement projects at pancreas transplant centers.
Williams et al (2022b) stated that graft-versus-host disease (GVHD) is a rare complication following solid organ transplant. These investigators presented a case of GVHD following SPKTx. The patient was diagnosed with a cutaneous biopsy after developing the classic symptoms of maculopapular rash, diarrhea, and pancytopenia. However, this patient had unexplained elevations in dd-cfDNA for months prior to the onset of GVHD symptoms. These researchers hypothesized that GVHD may be associated with elevated dd-cfDNA as a result of massive donor lymphocyte proliferation and turnover. The authors concluded that further investigation is needed because earlier diagnosis and treatment could improve outcomes in an otherwise lethal disease.
Ventura-Aguiar et al (2022) noted that pancreas graft status in SPKTx is currently examined by non-specific biochemical markers (e.g., amylase or lipase). Identifying a non-invasive biomarker with good sensitivity in detecting early pancreas graft rejection could improve SPKTx management. In a pilot study, these researchers examined dd-cfDNA performance in predicting biopsy-proven AR (P-BPAR) of the pancreas graft in a cohort of 36 SPKTx recipients with biopsy-matched plasma samples. dd-cfDNA was measured using the Prospera test (Natera, Inc.) and reported both as a fraction of the total cfDNA (fraction; %) and as concentration in the recipient's plasma (quantity; copies/ml). In the absence of P-BPAR, dd-cfDNA was significantly higher in samples collected within the first 45 days following SPKTx compared with those measured afterward (median of 1.00 % versus 0.30 %; median of 128.2 versus 35.3 cp/ml, respectively with both; p = 0.001). In samples obtained beyond day 45, P-BPAR samples presented a significantly higher dd-cfDNA fraction (0.83 % versus 0.30 %; p = 0.006) and quantity (81.3 cp/ml versus 53.3 cp/ml; p = 0.001) than stable samples. Incorporating dd-cfDNA quantity along with dd-cfDNA fraction out-performed dd-cfDNA fraction alone to detect AR. Notably, when using a quantity cut-off of 70 cp/ml, dd-cfDNA detected P-BPAR with a sensitivity of 85.7 % and a specificity of 93.7 %, which was more accurate than current biomarkers (area under curve [AUC] of 0.89 for dd-cfDNA (cp/ml) compared with 0.74 of lipase and 0.46 for amylase). The authors concluded that dd-cfDNA measurement via a simple non-invasive blood test could be incorporated into clinical practice to help inform graft management in SPKTx patients. These preliminary findings from a pilot study need to be validated by well-designed studies.
Furthermore, an UpToDate review on “Pancreas-kidney transplantation in diabetes mellitus: Pancreas allograft rejection” (Alhamad et al, 2022) does not mention the use of donor-derived cell-free DNA as a management option.
Institut Georges Lopez-1 (IGL-1) Graft Preservation Solution
Igreja and associates (2018) noted that graft preservation continues to be one of the main pillars of pancreas transplantation (PT). Surgical complications, possibly caused or facilitated by organ damage during preservation, continue to occur more frequently after PT than for any other abdominal organ. During the past few years, the Georges Lopez Institute preservation solution (IGL-1) has been introduced with satisfactory results for the perfusion and cold storage of abdominal grafts such as kidney and liver. In a retrospective study, these researchers analyzed aspects related to 47 PTs with the use of IGL-1 as the only preservation solution performed from January 2012 to September 2017 at Hospital Santa Isabel, Blumenau, Brazil. Considering the 46 transplanted patients (1 patient underwent 2 PTs), graft loss followed by death occurred in 2 patients: 1 due to pancreatic thrombosis, and 1 due to sepsis. In addition, a 3rd patient died with a functioning graft due to sepsis of an infected hematoma. In 1 patient, graft loss occurred due to pancreatic thrombosis and was later re-transplanted. One patient presented post-transplantation pancreatitis. The overall survival (OS) of patients in 1 month after transplantation was 95.7 %, and graft survival in the 1st month was 93.6 %. The authors concluded that in all patients transplanted with the use of IGL-1, normalization of pancreatic function occurred early after re-perfusion, there was no delayed graft function, and all transplanted patients maintained a non-insulin-dependent status after transplantation. These investigators stated that the use of IGL-1 as preservation solution for PT was safe and effective.
In a systematic review, Habran and colleagues (2020) examined published data on the effectiveness of IGL-1 as a preservation solution for kidney and pancreas grafts. These researchers carried out a systematic literature search of PubMed, Embase, Web of Science, and the Cochrane Library databases. Human studies evaluating the effects of IGL-1 preservation solution in kidney and/or pancreas transplantation were included. Outcome data on kidney and pancreas graft function were extracted. Of 1,513 unique articles identified via the search strategy, 4 articles could be included in the systematic review. Of these, 2 retrospective studies reported on the outcome of IGL-1 compared to University of Wisconsin (UW) solution in kidney transplantation. These showed kidneys preserved in IGL-1 had improved early function (2 weeks post-transplant) compared to UW. Follow-up was limited to 1 year and showed similar graft and patient survival rates when reported. Two case-series studies reported acceptable early outcomes (up to 1 month) of SPK transplantation after storage in IGL-1. As only 4 clinical articles were found, these investigators widened the search to include 4 eligible large animal studies; 3 compared IGL-1 with UW in pig kidney transplant models with inconclusive or mildly positive results; 1 pig PT study suggested better early outcome with IGL-1 compared to UW. The authors concluded that the limited published clinical data appeared to suggest that IGL-1 is a safe and promising preservation solution for the static cold storage of kidney and pancreas grafts. However, because there are no large data series available, it is currently unclear whether outcomes after transplantation of kidney and pancreas preserved with IGL-1 are equivalent to those obtained with UW or other commonly used abdominal preservation solutions. These researchers stated that additional well-designed studies and, ideally RCTs, are needed to demonstrate equivalence or superiority of one solution over the other.
The authors stated that this study had several drawbacks. As with all systematic reviews, it was possible that relevant articles were not identified although this was unlikely since a broad search strategy was designed in collaboration with an experienced librarian. Also as clinical work proved to be scarce, these researchers expanded the search as widely as possible to include published abstracts, reports in other languages as well as large animal studies. Risk of bias was assessed as high for all clinical studies, emphasizing that available data should be interpreted with caution. Studies reporting on large-animal had a low risk on performance and detection bias. However, many details with regard to sequence generation, allocation concealment and selective outcome reporting were not reported, making it difficult to evaluate risk of selection and reporting bias adequately.
Furthermore, an UpToDate review on “Overview of intestinal and multivisceral transplantation” (Khan and Selvaggi, 2020) states that “The organs are harvested and generally preserved in either University of Wisconsin solution (UW solution) or histidine-tryptophane-ketoglutarate solution. Cold ischemia time is kept to a minimum by coordinating timing of the donor operation with the recipient patient's surgery team”. This review does not mention IGL-1 as a preservation agent.
Induction Immunosuppression for Simultaneous Pancreas-Kidney Transplant
Kamarajah et al (2021) noted that induction immunosuppression for SPK transplantation has helped reduce graft loss due to early rejection. Both thymoglobulin and interleukin 2 (IL-2) receptor antagonists are the most commonly used induction agents; however, some high-volume centers prefer alemtuzumab. In a network meta-analysis, these researchers compared different induction regimens for SPK transplantation in terms of both pancreas and patient graft survival; and evaluated acute rejection (AR). They carried out a systematic review to identify randomized clinical trials up to October 31, 2019, that examined induction regimens for SPK transplantation. Study characteristics, post-operative data (patient, pancreas, and kidney graft survival), complications (e.g., bleeding), infection rates, and malignancy rates were extracted. These investigators compared all regimens using random effects network meta-analyses to maintain randomization within trials. This study identified 7 randomized clinical trials that involved 536 patients, which reported 5 induction regimens. These regimens included anti-thymocyte globulin (97 patients), alemtuzumab (42 patients), 2 doses (113 patients) or 5 doses (164 patients) of daclizumab, and no induction therapy (120 patients). In the network meta-analysis, a regimen with 2 doses of daclizumab was consistently ranked 1st for patient survival and kidney and pancreas graft survival. In contrast, alemtuzumab was ranked best for AR (both pancreas and kidney). Rates of major infection (i.e., CMV) and malignancy were reported in 3 studies, precluding a reliable analysis. The authors concluded that daclizumab with 2 doses, given before SPK transplantation, was associated with the best rates of patient and graft survival. Despite the recent withdrawal of daclizumab, an alternative anti-IL-2 induction regimen (basiliximab) has demonstrated promising results in non-randomized series, warranting that further high-quality, large-scale randomized clinical trials are still needed.
Outcomes of Type 1 Diabetics after Kidney Transplant Alone Compared to Simultaneous Pancreas-Kidney Transplant
Hedley et al (2022) stated that donor and other differences mean understanding drivers of transplant survival for patients with type 1 diabetes mellitus (T1DM) is challenging. These researchers compared outcomes of SPK transplantation over kidney transplantation alone for patients with end-stage kidney disease (ESKD) and T1DM. They carried out a population-based cohort study comparing outcomes from kidney alone and SPK using registry data. Study population was patients in Australia and New Zealand with T1DM and ESKD who received a kidney transplant in 1984 to 2016. Primary outcomes were time to kidney transplant failure and all-cause death. Secondary outcomes were time to cardiovascular and non-cardiovascular death. These researchers compared adjusted survival using Cox regression (hazard ratio [HR] and 95 % CI). Of 1,295 T1DM patients receiving a transplant, 430 (33 %) received deceased donor kidney, 172 (13 %) received living donor kidney, and 693 (54 %) received SPK. Compared to deceased donor kidney, SPK recipients had 40 % lower rate of kidney transplant failure (adjusted HR 0.60; 95 % CI: 0.45 to 0.81; p = 0.001) and 34 % lower mortality (adjusted HR 0.66; 95 % CI: 0.53 to 0.83; p < 0.001), driven by 49 % reduction in cardiovascular mortality (adjusted HR 0.51; 95 % CI: 0.36 to 0.72; p < 0.001). SPK recipients had similar reductions in transplant failure and mortality compared to living kidney recipients, after adjusting for transplant timing. The authors concluded that for patients with T1DM, SPK provided improved transplant survival as well as OS compared to deceased donor kidney alone. Living donor kidneys may perform just as well as SPK if waiting times were short.
Heparin Thromboprophylaxis in Pancreas-Kidney Transplantation
Li et al (2023) noted that thrombosis is a leading causes of pancreas graft loss following SPK, PAK, and PTA. There remains no standardized thromboprophylaxis protocol. In a systematic review and meta-analysis, these investigators examined the impact of heparin thromboprophylaxis on the incidence of pancreas thrombosis, pancreas graft loss, bleeding, and secondary outcomes in SPK, PAK, and PTA. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, these researchers systematically searched BIOSIS, PubMed, Cochrane Library, Embase, Medline, and Web of Science on April 21, 2021. Primary peer-reviewed studies that met inclusion criteria were included. Two methods of quantitative synthesis were carried out to account for comparative and non-comparative studies. These researchers included 11 studies, comprising of 1,122 patients in the heparin group and 236 patients in the no-heparin group. When compared to the no-heparin control, prophylactic heparinization significantly decreased the risk of early pancreas thrombosis and pancreas loss for SPK, PAK and PTA without increasing the incidence of bleeding or acute return to the operating room. Heparin thromboprophylaxis yields an approximate 2-fold reduction in both pancreas thrombosis and pancreas loss for SPK, PAK and PTA. These investigators reported the dosage, frequency, and duration of heparin administration to consolidate the available evidence. The authors concluded that with early post-operative complications, such as pancreas graft thrombosis, persisting as a leading cause for graft loss, heparin thromboprophylaxis holds promise for enhancing graft survival without imposing additional postoperative complications. Moreover, these investigators stated that future research that prospectively compares the impact of heparin to that of a no-heparin control is needed. Given that all the comparative studies in this review were published within the past decade, this suggests an influx of higher quality studies examining this subject in recent times. These researchers foresee more high-quality studies will become published in the near future, which will warrant additional meta-analyses.
Appendix
The Cockcroft-Gault formula for calculation of creatinine clearance is now generally accepted as superior to actual measured creatinine clearance as determined by a 24-hour urine collection, due to inherent inaccuracies and collection difficulties. The formula is as follows:
Cockcroft-Gault Formula |
---|
Estimated creatinine clearance (ml/min) for males: 140 minus age multiplies weight (kg) divided by serum creatinine (mg/dL) multiplies 72 |
Estimated creatinine clearance (ml/min) for females: 0.85 multiplies 140 minus age multiplies weight (kg) divided by serum creatinine (mg/dL) multiplies 72 Estimated creatinine clearance (ml/min) for females: 0.85 ((140 - age) x weight (kg)) serum creatinine (mg/dL) x 72 |
References
The above policy is based on the following references:
- Alhamad T, Kukla A, Stratta RJ. Pancreas-kidney transplantation in diabetes mellitus: Pancreas allograft rejection. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2022.
- American Diabetes Association. Pancreas transplantation for patients with type 1 diabetes (Position Statement). Diabetes Care. 2003;26(Suppl 1):S120.
- Andres A. Indications and contraindications of living-donor kidney transplantation. Nefrologia. 2010;30 Suppl 2:30-38.
- Arjona-Sanchez A, Rodríguez-Ortiz L, Sanchez-Hidalgo JM, et al. Intraoperative heparinization during simultaneous pancreas-kidney transplantation: Is it really necessary? Transplant Proc. 2018;50(2):673-675.
- Barlow AD, Saeb-Parsy K, Watson CJ. An analysis of the survival outcomes of simultaneous pancreas and kidney transplantation compared to live donor kidney transplantation in patients with type 1 diabetes: A UK Transplant Registry study. Transpl Int. 2017;30(9):884-892.
- Belmonte AA. Transplant strategies for diabetic renal patients. EDTNA ERCA J. 2004;30(3):157-162.
- Cantarovich D, Murat A, Krempf M, et al. Simultaneous pancreas and kidney transplantation in a type II (non-insulin-dependent) diabetic uremic patient requiring pregraft insulin therapy. Transplant Proc. 1990;22(2):662.
- Chan CM, Chim TM, Leung KC, et al. Simultaneous pancreas and kidney transplantation as the standard surgical treatment for diabetes mellitus patients with end-stage renal disease. Hong Kong Med J. 2016;22(1):62-69.
- Cicalese L, Giacomoni A, Rastellini C, Benedetti E. Pancreatic transplantation: A review. Int Surg. 1999;84(4):305-312.
- Cohen DJ, Sung RS. Simultaneous kidney-pancreas transplantation. Minerva Urol Nefrol. 2007;59(3):379-393.
- Diakoff E. Glucose metabolism after pancreas-kidney transplantation. Curr Diab Rep. 2008;8(4):310-316.
- Elkhammas EA, Demirag A, Henry ML. Simultaneous pancreas-kidney transplantation at Ohio State University Medical Center. Clinical Transplantation 1999, JM Cecka, PI Teraski, eds. Los Angeles, CA: UCLA Immunogenetics Center; 2000:211-215 (cited in Institute for Clinical Systems Improvement (ICSI). Pancreas transplant for insulin-dependent diabetes. Technology Assessment Report No. 4. Bloomington, MN: ICSI; October 2003).
- Elliott MD, Kapoor A, Parker MA, et al. Improvement in hypertension in patients with diabetes mellitus after kidney/pancreas transplantation. Circulation. 2001;104(5):563-569.
- Farney AC, Cho E, Schweitzer EJ, et al. Simultaneous cadaver pancreas living-donor kidney transplantation: A new approach for the type 1 diabetic uremic patient. Ann Surg. 2000;232(5):696-703.
- Farney AC, Doares W, Rogers J, et al. A randomized trial of alemtuzumab versus antithymocyte globulin induction in renal and pancreas transplantation. Transplantation. 2009;88(6):810-819.
- Fiorina P, Vezzulli P, Bassi R, et al. Near normalization of metabolic and functional features of the central nervous system in type 1 diabetic patients with end-stage renal disease after kidney-pancreas transplantation. Diabetes Care. 2012;35(2):367-374.
- Friedman AL, Friedman EA. Pancreas transplantation for type 2 diabetes at U.S. transplant centers. Diabetes Care. 2002;25(10):1896.
- Friedman AL. Appropriateness and timing of kidney and/or pancreas transplants in type 1 and type 2 diabetes. Adv Ren Replace Ther. 2001;8(1):70-82.
- Gerber PA, Pavlicek V, Demartines N, et al. Simultaneous islet-kidney vs pancreas-kidney transplantation in type 1 diabetes mellitus: A 5 year single centre follow-up. Diabetologia. 2008;51(1):110-119.
- Gruessner AC, Laftavi MR, Pankewycz O, Gruessner RWG. Simultaneous pancreas and kidney transplantation - Is it a treatment option for patients with type 2 diabetes mellitus? An analysis of the International Pancreas Transplant Registry. Curr Diab Rep. 2017;17(6):44.
- Habran M, De Beule J, Jochmans I. IGL-1 preservation solution in kidney and pancreas transplantation: A systematic review. PLoS One. 2020;15(4):e0231019.
- Health Council of the Netherlands Gezondheidsraad (GR). Kidney-pancreas transplantation. Rijswijk, The Netherlands: Health Council of the Netherlands Gezondheidsraad (GR); 1997.
- Hedley JA, Kelly PJ, Webster AC, et al. Patient and kidney transplant survival in type 1 diabetics after kidney transplant alone compared to simultaneous pancreas-kidney transplant. ANZ J Surg. 2022;92(7-8):1856-1862.
- Holohan T. Simultaneous pancreas-kidney and sequential pancreas-after-kidney transplantation. Health Technology Assessment No. 4. AHCPR Pub. No. 95-0065. Bethesda, MD: Agency for Healthcare Research and Quality (AHRQ); August 1995.
- Hricik DE. Kidney-pancreas transplantation for diabetic nephropathy. Semin Nephrol. 2000;20(2):188-198.
- Humar A, Ramcharan T, Kandaswamy R, et al. Pancreas after kidney transplants. Am J Surg. 2001;182(2):155-161.
- Humar A, Sutherland DE, Ramcharan T, et al. Optimal timing for a pancreas transplant after a successful kidney transplant. Transplantation. 2000;70(8):1247-1250.
- Igreja MR, Wiederkehr JC, Wiederkehr BA, et al. Use of Georges Lopez Institute preservation solution IGL-1 in pancreas transplantation: A series of 47 cases. Transplant Proc. 2018;50(3):702-704.
- Institute for Clinical Systems Improvement (ICSI). Pancreas transplant for insulin-dependent diabetes. Technology Assessment Report No. 4. Bloomington, MN: ICSI; October 2003.
- Israni AK. Quality of life after transplantation for patients with diabetes and renal dysfunction. Transplantation. 2001;72(5):969-970.
- Kahl A, Bechstein WO, Frei U. Trends and perspectives in pancreas and simultaneous pancreas and kidney transplantation. Curr Opin Urol. 2001;11(2):165-174.
- Kamarajah SK, Bundred JR, Manas D, White SA. A network meta-analysis of induction immunosuppression for simultaneous pancreas-kidney transplant from randomized clinical trials. Exp Clin Transplant. 2021;19(5):397-404.
- Khan FA, Selvaggi G. Overview of intestinal and multivisceral transplantation. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed May 2020.
- Kaufman DB, Leventhal JR, Elliott MD, et al. Pancreas transplantation at Northwestern University. Clin Transpl. 2000;239-246.
- Klein CL, Robertson RP. Patient selection for and immunologic issues relating to kidney-pancreas transplantation in diabetes mellitus. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed April 2014.
- Knight RJ, Graviss EA, Nguyen DT, et al. Conversion from tacrolimus-mycophenolate mofetil to tacrolimus-mTOR immunosuppression after kidney-pancreas transplantation reduces the incidence of both BK and CMV viremia. Clin Transplant. 2018;32(6):e13265.
- Knight SR, Thorne A, Lo Faro ML. Donor-specific cell-free DNA as a biomarker in solid organ transplantation. A systematic review. Transplantation. 2019;103(2):273-283.
- Kobayashi T, Gruessner AC, Wakai T, Sutherland DE. Three types of simultaneous pancreas and kidney transplantation. Transplant Proc. 2014;46(3):948-953.
- Koznarova R, Saudek F, Hrachovinova T, et al. The quality of life of pancreas recipients with type-1 diabetes. Transplant Proc. 2001;33(1-2):1890.
- Kronson JW, Gillingham KJ, Sutherland DE, Matas AJ. Renal transplantation for type II diabetic patients compared with type I diabetic patients and patients over 50 years old: a single-center experience. Clin Transplant. 2000;14(3):226-234.
- Lehmann R, Graziano J, Brockmann J, et al. Glycemic control in simultaneous islet-kidney versus pancreas-kidney transplantation in type 1 diabetes: A prospective 13-year follow-up. Diabetes Care. 2015;38(5):752-759.
- Lerner SM. Kidney and pancreas transplantation in type 1 diabetes mellitus. Mt Sinai J Med. 2008;75(4):372-384.
- Li EA, Farrokhi K, Zhang MY, et al. Heparin thromboprophylaxis in simultaneous pancreas-kidney transplantation: A systematic review and meta-analysis of observational studies. Transpl Int. 2023;36:10442.
- Light JA, Barhyte DY. Simultaneous pancreas-kidney transplants in type I and type II diabetic patients with end-stage renal disease: Similar 10-year outcomes. Transplant Proc. 2005;37(2):1283-1284.
- MacCraith E, Davis NF, Browne C, et al. Simultaneous pancreas and kidney transplantation: Incidence and risk factors for amputation after 10-year follow-up. Clin Transplant. 58. 2017;31(6).
- Marcacuzco A, Jimenez-Romero C, Manrique A, et al. Outcome of patients with hemodialysis or peritoneal dialysis undergoing simultaneous pancreas-kidney transplantation. Comparative study. Clin Transplant. 2018;32(6):e13268.
- Margreiter C, Pratschke J, Margreiter R. Immunological monitoring after pancreas transplantation. Curr Opin Organ Transplant. 2013;18(1):71-75.
- Ming CS, Chen ZH. Progress in pancreas transplantation and combined pancreas-kidney transplantation. Hepatobiliary Pancreat Dis Int. 2007;6(1):17-23.
- Montero N, Webster AC, Royuela A, et al. Steroid avoidance or withdrawal for pancreas and pancreas with kidney transplant recipients. Cochrane Database Syst Rev. 2014;9:CD007669.
- Morath C, Schmied B, Mehrabi A, et al. Simultaneous pancreas-kidney transplantation in type 1 diabetes. Clin Transplant. 2009;23 Suppl 21:115-120.
- Nath DS, Gruessner AC, Kandaswamy R, et al. Outcomes of pancreas transplants for patients with type 2 diabetes mellitus. Clin Transplant. 2005;19(6):792-797.
- National Health Service (NHS), UKT Kidney and Pancreas Advisory Group. National protocol for assessment of kidney and pancreas transplant patients. Bristol, UK: UK Transplant; September 2003.
- Ojo AO, Meier-Kriesche HU, Arndorfer JA, et al. Long-term benefit of kidney-pancreas transplants in type 1 diabetics. Transplant Proc. 2001;33(1-2):1670-1672.
- Palmer S, McGregor DO, Strippoli GF. Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev. 2007;(3):CD005015.
- Pavlakis M, Khwaja K, Mandelbrot D, et al. Renal allograft failure predictors after PAK transplantation: Results from the New England Collaborative Association of Pancreas Programs. Transplantation. 2010;89(11):1347-1353.
- Philosophe B, Farney AC, Schweitzer EJ, et al. Simultaneous pancreas-kidney (SPK) and pancreas living-donor kidney (SPLK) transplantation at the University of Maryland. Clin Transpl. 2000;211-216.
- Pirson Y, Vandeleene B, Squifflet JP. Kidney and kidney-pancreas transplantation in diabetic recipients. Diabetes Metab. 2000;26 Suppl 4:86-89.
- Pox C, Ritzel R, Busing M, et al. Combined pancreas and kidney transplantation in a lean type 2 diabetic patient. Effects on insulin secretion and sensitivity. Exp Clin Endocrinol Diabetes. 2002;110(8):420-424.
- Rayhill SC, D'Alessandro AM, Odorico JS, et al. Simultaneous pancreas-kidney transplantation and living related donor renal transplantation in patients with diabetes: Is there a difference in survival? Ann Surg. 2000;231(3):417-423.
- Reddy KS, Stablein D, Taranto S, et al. Long-term survival following simultaneous kidney-pancreas transplantation versus kidney transplantation alone in patients with type 1 diabetes mellitus and renal failure. Transplant Proc. 2001;33(1-2):1659-1660.
- Robertson RP, Davis C, Larsen J, et al. Pancreas and islet transplantation for patients with diabetes (Technical Review). Diabetes Care. 2000;23:112-116.
- Schulz T, Pries A, Caliebe A, Kapischke M. Long-term survival after simultaneous pancreas-kidney transplantation with primary function of at least one year -- a single-center experience. Ann Transplant. 2014;19:106-111.
- Stratta RJ, Shokouh-Amiri MH, Egidi MF, et al. Simultaneous kidney-pancreas transplant with systemic-enteric versus portal-enteric drainage. Transplant Proc. 2001;33(1-2):1661-1662.
- Sudan D, Sudan R, Stratta R. Long-term outcome of simultaneous kidney-pancreas transplantation: Analysis of 61 patients with more than 5 years follow-up. Transplantation. 2000;69(4):550-555.
- Sutherland DE, Gruessner RW, Gruessner AC. Pancreas transplantation for treatment of diabetes mellitus. World J Surg. 2001;25(4):487-496.
- Ventura-Aguiar P, Ramirez-Bajo MJ, Rovira J, et al. Donor-derived cell-free DNA shows high sensitivity for the diagnosis of pancreas graft rejection in simultaneous pancreas-kidney transplantation. Transplantation. 2022;106(8):1690-1697.
- White SA, Shaw JA, Sutherland DE. Pancreas transplantation. Lancet. 2009;373(9677):1808-1817..
- Williams MD, Fei M, Schadde E, et al. Early experience using donor-derived cell-free DNA for surveillance of rejection following simultaneous pancreas and kidney transplantation. Transplant Direct. 2022a;8(5):e1321.
- Williams MD, Thomas J, Paner A, et al. Can donor-derived cell-free DNA detect graft-versus-host disease in solid organ transplantation: A case report. Transplant Proc. 2022b;54(1):176-179.
- Wiseman AC. Simultaneous pancreas kidney transplantation: A critical appraisal of the risks and benefits compared with other treatment alternatives. Adv Chronic Kidney Dis. 2009;16(4):278-287.
- Ziaja J, Kowalik AP, Kolonko A, et al. Type 1 diabetic patients have better endothelial function after simultaneous pancreas-kidney transplantation than after kidney transplantation with continued insulin therapy. Diab Vasc Dis Res. 2018;15(2):122-130.