Role of gastric peroral endoscopic myotomy (GPOEM) in chronic gastroparesis management after pancreas transplantation.

Gastroparesis is a common complaint among patients with diabetes. Symptoms tend to improve following successful pancreas transplantation (PTx), but persist despite euglycemia in a subset of patients. We aimed to assess the benefit of gastric peroral endoscopic myotomy (G-POEM) in persistent gastroparesis following PTx. This was a single center retrospective review of all patients who underwent G-POEM for persistent gastroparesis following PTx. Patient demographics, pre and post procedure perception of symptom severity according to the patient assessment of upper gastrointestinal symptoms severity index (PAGI-SYM), gastroparesis cardinal symptom index (GCSI) score, and 36-item short form survey (SF36) score along with gastric emptying scintigraphy (GES) were analyzed. Seven PTx recipients underwent G-POEM for persistent gastroparesis symptoms. The majority were female. All reported nausea/vomiting, abdominal pain, bloating, and post prandial fullness prior to G-POEM. The post procedure survey scores improved in all patients although this was not significant. The improvement in gastric emptying on GES was statistically significant. G-POEM is a relatively new treatment option for gastroparesis. While it requires specialized proceduralist and training, we have documented improvement in the management of symptoms. With increasing experience, we anticipate more significant benefit in post PTx patients with persistent symptoms of gastroparesis undergoing G-POEM.

Simultaneous pancreas and kidney transplant after bilateral lung transplant for a recipient with cystic fibrosis.

Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. Lung transplantation is the only available therapy that deals definitively with the end-stage pulmonary disease and has become the treatment of choice for some of these patients. As patients with CF are living longer, extrapulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency and CF-related diabetes (CFRD). Both of these can be managed through pancreas transplantation. We have previously reported our series of three simultaneous lung and pancreas transplants in patients with CF, which were complicated by surgical issues for both the thoracic and abdominal portions, rejection and resistant infections with disappointing long-term survival. Based on these results, a sequential approach was adopted: first, the thoracic transplant; and second, once the patient has recovered, the abdominal transplants. This is the first reported case of pancreas and kidney transplantation performed after a lung transplant in a patient with CF. It demonstrates a successful approach to treating CF with a lung transplant, and in an effort to improve the patient's long-term outcome, treating CFRD and pancreatic enzyme insufficiency, with a subsequent pancreas transplant.

Distal allograft pancreatectomy for graft salvage after pancreas transplantation.

Early pancreas allograft failure most commonly results from vascular thrombosis. Immediate surgical intervention may permit pancreas allograft salvage, typically requiring thrombectomy. In cases of partial allograft necrosis secondary to splenic arterial thrombosis, distal allograft pancreatectomy may allow salvage of at least half of the pancreas allograft with retention of function. We retrospectively reviewed four cases of simultaneous pancreas and kidney recipients who required distal allograft pancreatectomy for splenic artery thrombosis with necrosis of the distal pancreas. Three of the four maintained long-term allograft function with euglycemia independent of insulin at six months to six years of follow-up, and all patients continue to maintain normal renal allograft function. Early diagnosis and early intervention are essential in order to salvage the pancreas allograft in the case of thrombosis. Distal allograft pancreatectomy can be performed safely and result in excellent long-term outcomes in select patients.

Pancreas transplantation for cystic fibrosis: A frequently missed opportunity.

Cystic fibrosis (CF) is an inherited autosomal recessive disorder. Despite optimized therapy, the majority of affected individuals ultimately die of respiratory failure. As patients with CF are living longer, extra-pulmonary manifestations may develop including pancreatic failure, which manifests as exocrine insufficiency, and CF-related diabetes (CFRD). Both of these can be managed through pancreas transplantation. Pancreas transplantation is usually performed in combination with another organ, most often with a kidney transplant for end-stage diabetic nephropathy. In the CF patient population, the two settings where inclusion of a pancreas transplant should be considered would be in combination with a lung transplant for CF pulmonary disease, or in combination with a liver for CF-related liver disease with cirrhosis. This report will discuss this topic in detail, including a review of the literature regarding combinations of lung/pancreas and liver/pancreas transplant.

Pancreas transplantation would be easy if the recipients were not diabetic: A practical guide to post-operative management of diabetic complications in pancreas transplant recipients.

Diabetes mellitus remains a major public health problem throughout the United States with over $300 billion spent in total cost of care annually. In addition to being a leading cost of kidney failure, diabetes causes a host of secondary hyperglycemic-related complications including gastroparesis and orthostatic hypotension. While pancreas transplantation has been established as an effective treatment for diabetes, providing long-term normoglycemia in recipients, the secondary complications of diabetes mellitus persist complicating the post-operative course of an otherwise successful pancreas transplantation. This review describes the mechanism and impact of diabetic gastroparesis and orthostatic hypotension in the post-operative course of pancreas transplant patients and analyzes the various treatment modalities, based on current data and extensive experience at our institution, to treat these respective complications. While gastroparesis and orthostatic hypotension remain challenging post-operative conditions, the establishment of institutional protocols and step-up treatment algorithms can help define more effective therapies.

Contrast Administration to the Deceased Kidney Donor Has No Impact on Post-Transplant Outcomes.

BACKGROUND: Contrast-induced acute kidney injury may occur in patients undergoing imaging studies. This study reviews all deceased kidney donors at a single center during a 15-y period to determine if donor contrast exposure results in contrast-induced acute kidney injury in the donor or is associated with worse outcomes in the transplant recipient. METHODS: Donor and recipient renal functions were recorded, including donor serum creatinine and recipient delayed graft function, creatinine clearance at 1 y, and early and late graft survival. Donor contrast exposure was recorded as the number of preprocurement contrasted studies. RESULTS: Donor and recipient records were available for 1394 transplants (88%). There were 51% of donors who received any contrasted study (38%, one study; 12%, two studies, and 1%, three studies). Donor contrast exposure was not associated with significant differences in preprocurement serum creatinine levels. Post-transplant, donor contrast exposure was associated with risk of neither delayed graft function (4% for all) nor early kidney graft loss. Creatinine clearance at 1 y was equivalent. Five-year Cox regression demonstrated higher graft survival for contrast-exposed grafts (P = 0.03). CONCLUSIONS: There is no negative effect of donor contrast administration on early and late kidney graft function. These findings included donor kidneys exposed to as many as three contrasted studies.

Pancreas transplantation following total pancreatectomy for chronic pancreatitis.

BACKGROUND: Total pancreatectomy for chronic pancreatitis leads to brittle diabetes and challenging glycemic control with half of all patients experiencing severe hypoglycemia, many requiring medical intervention or hospitalization. Pancreas transplantation has the potential to manage both the endocrine and the exocrine insufficiency in this patient population. METHODS: Between June 1, 2005, and July 1, 2016, 8 patients with brittle diabetes following total pancreatectomy underwent pancreas transplantation. All grafts had systemic venous and enteric exocrine drainage. Data included demographics, graft and patient survival, pre- and post-transplant supplementation with pancreatic enzymes, and narcotic usage. RESULTS: Patient survival rate at 1 and 3 years was 88%. Pancreas graft survival rate of those alive at 1 year was 100% and 86%, respectively. About 75% of these patients remained insulin-free until their time of death, loss of follow-up, or present day. Of the patients with maintained graft function at 3 years, none required further hospitalization for glycemic control. About 75% of these patients have also maintained exocrine function without pancreatic enzyme supplementation. CONCLUSIONS: Pancreas transplant can treat both exocrine and endocrine insufficiency and give long-term insulin-free survival and should be considered as a viable treatment option for patients who have undergone total pancreatectomy for chronic pancreatitis.

Multi-platform assessment of transcriptional profiling technologies utilizing a precise probe mapping methodology.

BACKGROUND: The arrival of RNA-seq as a high-throughput method competitive to the established microarray technologies has necessarily driven a need for comparative evaluation. To date, cross-platform comparisons of these technologies have been relatively few in number of platforms analyzed and were typically gene name annotation oriented. Here, we present a more extensive and yet precise assessment to elucidate differences and similarities in performance of numerous aspects including dynamic range, fidelity of raw signal and fold-change with sample titration, and concordance with qRT-PCR (TaqMan). To ensure that these results were not confounded by incompatible comparisons, we introduce the concept of probe mapping directed "transcript pattern". A transcript pattern identifies probe(set)s across platforms that target a common set of transcripts for a specific gene. Thus, three levels of data were examined: entire data sets, data derived from a subset of 15,442 RefSeq genes common across platforms, and data derived from the transcript pattern defined subset of 7,034 RefSeq genes. RESULTS: In general, there were substantial core similarities between all 6 platforms evaluated; but, to varying degrees, the two RNA-seq protocols outperformed three of the four microarray platforms in most categories. Notably, a fourth microarray platform, Agilent with a modified protocol, was comparable, or marginally superior, to the RNA-seq protocols within these same assessments, especially in regards to fold-change evaluation. Furthermore, these 3 platforms (Agilent and two RNA-seq methods) demonstrated over 80% fold-change concordance with the gold standard qRT-PCR (TaqMan). CONCLUSIONS: This study suggests that microarrays can perform on nearly equal footing with RNA-seq, in certain key features, specifically when the dynamic range is comparable. Furthermore, the concept of a transcript pattern has been introduced that may minimize potential confounding factors of multi-platform comparison and may be useful for similar evaluations.

Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model.

Xenotransplantation has the potential to alleviate the organ shortage that prevents many patients with end-stage renal disease from enjoying the benefits of kidney transplantation. Despite significant advances in other models, pig-to-primate kidney xenotransplantation has met limited success. Preformed anti-pig antibodies are an important component of the xenogeneic immune response. To address this, we screened a cohort of 34 rhesus macaques for anti-pig antibody levels. We then selected animals with both low and high titers of anti-pig antibodies to proceed with kidney transplant from galactose-α1,3-galactose knockout/CD55 transgenic pig donors. All animals received T-cell depletion followed by maintenance therapy with costimulation blockade (either anti-CD154 mAb or belatacept), mycophenolate mofetil, and steroid. The animal with the high titer of anti-pig antibody rejected the kidney xenograft within the first week. Low-titer animals treated with anti-CD154 antibody, but not belatacept exhibited prolonged kidney xenograft survival (>133 and >126 vs. 14 and 21 days, respectively). Long-term surviving animals treated with the anti-CD154-based regimen continue to have normal kidney function and preserved renal architecture without evidence of rejection on biopsies sampled at day 100. This description of the longest reported survival of pig-to-non-human primate kidney xenotransplantation, now >125 days, provides promise for further study and potential clinical translation.

Double knockout pigs deficient in N-glycolylneuraminic acid and galactose α-1,3-galactose reduce the humoral barrier to xenotransplantation.

BACKGROUND: Clinical xenotransplantation is not possible because humans possess antibodies that recognize antigens on the surface of pig cells. Galα-1,3-Gal (Gal) and N-glycolylneuraminic acid (Neu5Gc) are two known xenoantigens. METHODS: We report the homozygous disruption of the α1, 3-galactosyltransferase (GGTA1) and the cytidine monophosphate-N-acetylneuraminic acid hydroxylase (CMAH) genes in liver-derived female pig cells using zinc-finger nucleases (ZFNs). Somatic cell nuclear transfer (SCNT) was used to produce healthy cloned piglets from the genetically modified liver cells. Antibody-binding and antibody-mediated complement-dependent cytotoxicity assays were used to examine the immunoreactivity of pig cells deficient in Neu5Gc and Gal. RESULTS: This approach enabled rapid production of a pig strain deficient in multiple genes without extensive breeding protocols. Immune recognition studies showed that pigs lacking both CMAH and GGTA1 gene activities reduce the humoral barrier to xenotransplantation, further than pigs lacking only GGTA1. CONCLUSIONS: This technology will accelerate the development of pigs for xenotransplantation research.

Fibronectin from alpha 1,3-galactosyltransferase knockout pigs is a xenoantigen.

BACKGROUND: Antibody-mediated rejection continues to be an obstacle for xenotransplantation despite development of α1,3-galactosyltransferase knockout (GTKO) pigs. Fibronectin (Fn) from GTKO pigs was identified as a xenoantigen in baboons. N-glycolylneuraminic acid (Neu5Gc), similar to galactose α1,3-galactose, is an antigenic carbohydrate found in pigs. We evaluated human antibody reactivity and performed initial antigenic epitope characterization of Fn from GTKO pigs. MATERIALS AND METHODS: GTKO pig aortic endothelial cells (AEC) were isolated and assessed for antibody-mediated complement-dependent cytotoxicity (CDC). Human and GTKO pig Fn were purified and analyzed using immunoblots. GTKO pig and human AEC absorbed human sera were assessed for CDC and anti-GTKO pig Fn antibodies. GTKO pig proteins were assessed for Neu5Gc. Immunoaffinity-purified human IgG anti-GTKO pig (hIgG-GTKOp) Fn using a GTKO pig Fn column were evaluated for cross-reactivity with other proteins. RESULTS: GTKO pig AEC had greater human antibody binding, complement deposition and CDC compared with allogeneic human AEC. Human sera absorbed with GTKO pig AEC resulted in diminished anti-GTKO pig Fn antibody. Neu5Gc was identified on GTKO pig Fn and other proteins. The hIgG-GTKOp Fn cross-reacted with multiple GTKO pig proteins and was enriched with anti-Neu5Gc antibody. CONCLUSIONS: Removal of antigenic epitopes from GTKO pig AEC would improve xenograft compatibility. GTKO pig Fn has antigenic epitopes, one identified as Neu5Gc, which may be responsible for pathology and cross-reactivity of hIgG-GTKOp Fn. Genetic knockout of Neu5Gc appears necessary to address significance and identification of non-Neu5Gc GTKO pig Fn antigenic epitopes.

Simultaneous Heart-kidney Transplant With Planned Delayed Implantation of the Kidney Graft After Ex Vivo Perfusion.

BACKGROUND: Simultaneous heart-kidney transplant (SHK) is an established option for patients with severe heart failure and chronic kidney disease. Recent studies in simultaneous liver-kidney transplantation demonstrate favorable outcomes achieved by delaying implantation of the kidney for over 24 h. This report describes a case series of consecutive patients listed for SHK who had planned delayed implantation of the kidney graft. METHODS: This case series represents a retrospective analysis of SHK patients extracted from the transplant database at a single center. RESULTS: There were 7 patients who underwent SHK during the study period. In all cases, kidney grafts were maintained on hypothermic ex vivo pulsatile perfusion for delayed implantation (mean cold ischemia 53 h [range, 31-69]). The first 5 patients had 100% 1-y heart and kidney graft survival with good function. Patient 6 was unstable on extracorporeal membrane oxygenation post-heart transplant. The kidney was implanted at 69 h, and the patient died soon thereafter. Patient 7 was also unstable on extracorporeal membrane oxygenation after heart transplant. The decision was made to implant the kidney into a backup kidney recipient. The heart transplant recipient subsequently died several days later, whereas the kidney was successfully transplanted in the alternate candidate. CONCLUSIONS: This case series highlights the potential utility of delayed kidney implantation in SHK patients. SHK with delayed renal transplant may provide an improved physiologic environment for renal transplant, which may result in improved early renal graft function. Delayed kidney transplant also provides the opportunity to transplant the kidney graft into an alternate candidate.

Epidemiology and Risk Factors for Invasive Fungal Infections in Pancreas Transplant in the Absence of Postoperative Antifungal Prophylaxis.

Background: Invasive fungal infections (IFIs) remain a rare yet dreaded complication following pancreas transplantation. Current guidelines recommend antifungal prophylaxis in patients with 1 or more risk factors. At our center, single-dose antifungal prophylaxis is administered in the operating room but none subsequently, regardless of risk factors. Here we evaluate the 1-year incidence, outcome, and risk factors associated with IFI following pancreas transplantation. Methods: A retrospective, single-center cohort study was conducted in patients who underwent pancreas transplantation between 1 January 2009 and 31 December 2019. Records were manually reviewed, and cases were adjudicated using consensus definitions. The 1-year cumulative incidence, mortality, and risk factors were analyzed by Kaplan-Meier method and differences between populations were assessed with Fisher test and Mann-Whitney U test. Results: Three hundred sixty-nine recipients were included. Twelve IFIs were identified: candidiasis (8), aspergillosis (2), histoplasmosis (1), and cryptococcosis (1). Intra-abdominal infections were the most common presentation (5), followed by bloodstream infections (3), disseminated disease (2), pulmonary disease (1), and invasive fungal sinusitis (1). Median time to IFI was 64 days (interquartile range, 30-234 days). One-year cumulative incidence was 3.25% (95% confidence interval, 1.86%-5.65%). There were no significant differences between patients with or without IFI regarding type of transplant (P = .17), posttransplant dialysis (P = .3), rejection (P = .5), cytomegalovirus serostatus (P = .45), or reoperation (P = .19). For patients with IFI, the 1-year graft and patient survival rates were 58% versus 95% (P < .0001) and 75% versus 98.6% (P < .001), respectively. Conclusions: Our study suggests that the use of a single-dose antifungal prophylaxis administered in the operating room but none subsequently does not result in an increased incidence of IFI following pancreas transplantation.

Deceased Donor Flush Volume Similar for Histidine-Tryptophan-Ketoglutarate and University of Wisconsin at a Single US Organ Procurement Organization: Adult and Pediatric Data.

BACKGROUND: Histidine-tryptophan-ketoglutarate (HTK) and University of Wisconsin (UW) solutions are the two primary solid-organ preservation solutions used in the United States (>95%), but flush volumes vary markedly by region and center. This study analyzes data from a single organ procurement organization (OPO) to determine the actual clinical flush volumes used for HTK and UW for liver and pancreas grafts. METHODS: All procurements at Indiana Donor Network were analyzed (2016-2020), and data were extracted from the on-site records. Variables included procuring center, solution, volumes, and vessels flushed. Brand and generic versions were considered equivalent. No clinical transplant outcomes were available. RESULTS: Data were analyzed from 875 liver and 192 pancreas procurements by over 70 U.S. centers representing 10 of 11 UNOS regions. The large majority of liver grafts were preserved with HTK (n=810, 93%; UW n=93, 7%). All liver donors received an aortic flush (100%), while portal vein flush was 14% in-situ and 88% back table. For liver grafts, the median volume of infused solution was less for HTK when compared to UW (4225mL vs 5500mL, p=0.04). For pancreas procurement, 100% received aortic flush of the graft, with median HTK and UW volumes being equivalent (3000mL; p=0.85). Pediatric organs were flushed with markedly higher weight-based volumes. CONCLUSIONS: Flush volumes for HTK and UW are similar at one midwestern OPO, with data comprised of procurements performed by centers from across the U.S. These data demonstrate that low-volume HTK flush is commonly used, and this practice may be considered as a cost-saving measure.

Revitalizing pancreas transplantation: creation of a hands-on training course for pancreas allograft procurement, backbench preparation, and transplantation.

Despite a steady increase in the number of organs available for transplant in the United States, over the last two decades there has been a precipitous decrease in the annual number of pancreas transplants performed. One overlooked consequence of this decline in pancreas transplant volume has been a decrease in experience in proper pancreas procurement and transplantation techniques for transplant surgeons as well as fewer trained abdominal transplant fellows entering the workforce certified for pancreas procurement and transplantation, with those achieving certification having less-developed judgment, skills, and experience. To augment current fellowship training and provide a concentrated experience in pancreas procurement and transplantation, the ASTS developed a hands-on surgical skills workshop focused on proper techniques for pancreas allograft procurement and backbench preparation.

Identification of human preformed antibody targets in GTKO pigs.

BACKGROUND: Human preformed antibodies continue to recognize porcine xenografts, despite the advent of α-galactosyltransferase knockout (GTKO) pigs. This study examined the potential reactivity of human preformed IgG and IgM antibodies toward antigens in the GTKO pig liver. METHODS: Human serum was analyzed for the concentration of IgG, IgM, anti-αgal antibody, anti-non-αgal antibody and cytotoxicity toward domestic and GTKO fibroblasts and liver sinusoidal endothelial cells (LSEC). We detected preformed antibodies in human serum directed toward GTKO pig liver cells and tissue samples using advanced proteomic techniques. The targets of preformed antibodies were identified by MALDI TOF TOF mass spectrometry and validated by confocal microscopy, immunoblot, and immunoprecipitation. RESULTS: Human serum used in this study contained 2.06 µg/ml IgG and 0.013 µg/ml IgM directed toward GTKO fibroblasts. Human IgG and IgM bound to GTKO LSEC in a dose-dependent manner and were cytotoxic. We detected 357 protein spots recognized by human IgG and 233 by human IgM. Two hundred and nineteen proteins were common to both human IgG and IgM. Mass spectrometry identified numerous immunoreactive proteins, of which 19 were membrane proteins on liver cells. The most significant to this study were α-enolase, CFTR, and E-cadherin, which were abundant in GTKO pig tissues and expressed on the surface of GTKO LSEC. Human IgG captured α-enolase, CFTR, and E-cadherin by immunoprecipitation validating the proteomic identification. CONCLUSION: These experiments indicate that several membrane antigens in GTKO pigs could be recognized directly by human IgG or IgM. Further studies on the contribution of these antigens to antibody-mediated xenograft rejection are necessary.

Cardiac rehabilitation in older adults: Apropos yet significantly underutilized.

Cardiac Rehabilitation (CR) is a comprehensive disease management program that utilizes exercise training, behavioral modification, education, and psychosocial counseling to optimize outcomes and functionality in patients with cardiovascular disease (CVD)1). While CR was initially designed as an exercise training and fitness program for younger patients, usually men, after debilitating hospitalizations for myocardial infarction or cardiac surgery, evidence has expanded to also include other types of CVD in women as well as men, including heart failure, valvular disease, and peripheral arterial disease2-4). As the population of older adults continues to expand, age-related CVD is endemic and is commonly associated with exercise decline, diminished quality of life, and dependence. CR has the potential to counterbalance these patterns, and therefore stands out as a particularly important consideration for older adults with CVD. Nevertheless, CR remains highly underutilized5,6). Novel approaches to CR including home-based and hybrid CR programs show promise for enhanced outreach to patients who may not otherwise participate. This review summarizes the current data available regarding CR in older adults with CVD with a focus on geriatric-specific complexities, current barriers to utilization, and approaches to enhance participation and effectiveness.

Adenovirus-Related Fulminant Liver Failure After Kidney Transplantation.

BACKGROUND Human adenovirus is a well-known pathogen that can potentially lead to severe infection in immunocompromised patients. Adenovirus infections in solid-organ transplant recipients can range from asymptomatic to severe, prolonged, disseminated disease, and have a significant impact on morbidity, mortality, and graft survival. The clinical manifestations vary from asymptomatic and flu-like illness to severe life-threatening viremia with multi-organ failure. Post-transplant adenovirus infection is well described in kidney recipients, but in adult liver transplant recipients the impact of the virus is not well described. In this report, a case of disseminated adenovirus infection with subsequent fatal acute liver failure in a post-kidney transplant patient is presented. CASE REPORT A 51-year-old man underwent a deceased kidney transplantation for focal segmental glomerulosclerosis. Shortly after the kidney transplantation, he received multiple plasmapheresis with additional steroid treatments for cellular rejection and reoccurrence of his primary kidney disease. Three weeks after the kidney transplant, he developed a disseminated adenovirus infection with subsequent acute liver failure. Despite the early diagnosis and aggressive treatment, the patient died. CONCLUSIONS Patients with organ transplantation with autoimmune background etiology are usually over-immunosuppressed to avoid early rejection. In this population, opportunistic infections are not rare. Fever, general malaise, and transplant organ dysfunction are the first signs of bacterial or viral infection. Early infectious diseases work-up, including tissue biopsy, is fundamental to establish a diagnosis. Broad antibiotic and possible antiviral aggressive treatment are mandatory.