Improving Health Equity in Living Donor Kidney Transplant: Application of an Implementation Science Framework.

BACKGROUND: Interventions to improve racial equity in access to living donor kidney transplants (LDKT) have focused primarily on patients, ignoring the contributions of clinicians, transplant centers, and health system factors. Obtaining access to LDKT is a complex, multi-step process involving patients, their families, clinicians, and health system functions. An implementation science framework can help elucidate multi-level barriers to achieving racial equity in LDKT and guide the implementation of interventions targeted at all levels. METHODS: We adopted the Pragmatic Robust Implementation and Sustainability Model (PRISM), an implementation science framework for racial equity in LDKT. The purpose was to provide a guide for assessment, inform intervention design, and support planning for the implementation of interventions. RESULTS: We applied 4 main PRISM domains to racial equity in LDKT: Organizational Characteristics, Program Components, External Environment, and Patient Characteristics. We specified elements within each domain that consider perspectives of the health system, transplant center, clinical staff, and patients. CONCLUSION: The applied PRISM framework provides a foundation for the examination of multi-level influences across the entirety of LDKT care. Researchers, quality improvement staff, and clinicians can use the applied PRISM framework to guide the assessment of inequities, support collaborative intervention development, monitor intervention implementation, and inform resource allocation to improve equity in access to LDKT.

A Historical Cohort in Kidney Transplantation: 55-Year Follow-Up of 72 HLA-Identical, Donor-Recipient Pairs.

The impact of HLA matching on graft survival has been well characterized in renal transplantation, with a higher degree of matching associated with superior graft survival. Additionally, living donor grafts are known to confer superior survival compared to those from deceased donors. The purpose of this study is to report our multi-decade institutional experience and outcomes for patients who received HLA-identical living donor grafts, which represent the most favorable scenario in kidney transplantation. We conducted a retrospective analysis of these graft recipients performed at a Duke University Medical Center between the years of 1965 and 2002. The recipients demonstrated excellent graft and patient survival outcomes, superior to a contemporary cohort, with median patient and graft survival of 24.2 and 30.9 years, respectively, among Duke recipients vs. 16.1 and 16.0 years in a cohort derived from national data. This study offers a broad perspective on the importance of HLA matching and graft type, and demonstrates a historical best-case-scenario in renal transplantation.

Coagulation, inflammation, and CD46 transgene expression in neonatal porcine islet xenotransplantation.

BACKGROUND: Thrombosis is a known consequence of intraportal islet transplantation, particularly for xenogeneic islets. To define the origins of thrombosis after islet xenotransplantation and relate it to early inflammation, we examined porcine islets transplanted into non-human primates using a dual-transplant model to directly compare islet characteristics. METHODS: α1,3-Galactosyltransferase gene-knockout (GTKO) islets with and without expression of the human complement regulatory transgene CD46 (hCD46) were studied. Biologically inert polyethylene microspheres were used to examine the generic pro-thrombotic effects of particle embolization. Immunohistochemistry was performed 1 and 24 hours after transplantation. RESULTS: Xeno-islet transplantation activated both extrinsic and intrinsic coagulation pathways. The intrinsic pathway was also initiated by microsphere embolization, while extrinsic pathway tissue factor (TF) and platelet aggregation were more specific to engrafted islets. hCD46 expression significantly reduced TF, platelet, fibrin, and factor XIIIa accumulation in and around islets but did not alter intrinsic factor activation. Layers of TF+ cells emerged around islets within 24 hours, particularly co-localized with vimentin, and identified as CD3+ and CD68+ cells inflammatory cells. CONCLUSIONS: These findings detail the origins of thrombosis following islet xenotransplantation, relate it to early immune activation, and suggest a role for transgenic hCD46 expression in its mitigation. Layers of TF-positive inflammatory cells and fibroblasts around islets at 24 hours may have important roles in the progressive events of thrombosis, inflammatory cell recruitment, rejection, and the ultimate outcome of transplanted grafts. These suggest that the strategies targeting these elements could yield more progress toward successful xenogeneic islet engraftment and survival.

Definition and Analysis of Textbook Outcome: A Novel Quality Measure in Kidney Transplantation.

BACKGROUND: "Textbook outcome" (TO) is a novel composite quality measure that encompasses multiple postoperative endpoints, representing the ideal "textbook" hospitalization for complex surgical procedures. We defined TO for kidney transplantation using a cohort from a high-volume institution. METHODS: Adult patients who underwent isolated kidney transplantation at our institution between 2016 and 2019 were included. TO was defined by clinician consensus at our institution to include freedom from intraoperative complication, postoperative reintervention, 30-day intensive care unit or hospital readmission, length of stay > 75th percentile of kidney transplant patients, 90-day mortality, 30-day acute rejection, delayed graft function, and discharge with a Foley catheter. Recipient, operative, financial characteristics, and post-transplant patient, graft, and rejection-free survival were compared between patients who achieved and failed to achieve TO. RESULTS: A total of 557 kidney transplant patients were included. Of those, 245 (44%) achieved TO. The most common reasons for TO failure were delayed graft function (N = 157, 50%) and hospital readmission within 30 days (N = 155, 50%); the least common was mortality within 90 days (N = 6, 2%). Patient, graft, and rejection-free survival were significantly improved among patients who achieved TO. On average, patients who achieved TO incurred approximately $50,000 less in total inpatient charges compared to those who failed TO. CONCLUSIONS: TO in kidney transplantation was associated with favorable post-transplant outcomes and significant cost-savings. TO may offer transplant centers a detailed performance breakdown to identify aspects of perioperative care in need of process improvement.

The Legacy of Joseph A. Moylan, M.D.: "It's About Everyone Else".

The history of modern American surgery is marked by larger-than-life pioneers who have made transformative contributions to our field. These extraordinary individuals have been known primarily for their technical and clinical mastery, development of novel surgical procedures and techniques, extraordinary abilities in the education and training of surgeons, and/or innovative discoveries in biomedical science. While mastery in clinical surgery, education, and research have come to characterize the consummate academic surgeon, challenging social inequities of today now demand deeper engagement in another vital arena. This historical account is the story of a truly exceptional surgeon and visionary who spent much of his life leading that very charge. Early in his career, Dr. Joseph Moylan recognized and embraced this obligation to go beyond the walls of the hospital and out into the community to combat social factors leading to adverse outcomes for at-risk young men. His legacy itself represents a vehicle for empowering youth confronted with barriers to educational opportunities and experiences. Furthermore, recounting Joe's journey conveys the over-arching thesis that surgeons have the opportunity-and, indeed, are well positioned-to engage more deeply with their communities, to lead efforts to address social determinants at their roots and to create a pipeline of bright young scholars and potential future surgeons.

The role of human CD46 in early xenoislet engraftment in a dual transplant model.

BACKGROUND: Membrane cofactor protein CD46 attenuates the complement cascade by facilitating cleavage of C3b and C4b. In solid organ xenotransplantation, organs expressing CD46 have been shown to resist hyperacute rejection. However, the incremental value of human CD46 expression for islet xenotransplantation remains poorly defined. METHODS: This study attempted to delineate the role of CD46 in early neonatal porcine islet engraftment by comparing Gal-knocked out (GKO) and hCD46-transgenic (GKO/CD46) islets in a dual transplant model. Seven rhesus macaques underwent dual transplant and were sacrificed at 1 hour (n = 4) or 24 hours (n = 3). Both hemilivers were recovered and fixed for immunohistochemistry (CD46, insulin, neutrophil elastase, platelet, IgM, IgG, C3d, C4d, CD68, Caspase 3). Quantitative immunohistochemical analysis was performed using the Aperio Imagescope. RESULTS: Within 1 hour of intraportal infusion of xenografts, no differences were observed between the two types of islets in terms of platelet, antibody, or complement deposition. Cellular infiltration and islet apoptotic activity were also similar at 1 hour. At 24 hours, GKO/CD46 islets demonstrated significantly less platelet deposition (P = 0.01) and neutrophil infiltration (P = 0.01) compared to GKO islets. In contrast, C3d (P = 0.38) and C4d (P = 0.45) deposition was equal between the two genotypes. CONCLUSIONS: Our findings suggest that expression of hCD46 on NPIs potentially provides a measurable incremental survival advantage in vivo by reducing early thrombo-inflammatory events associated with instant blood-mediated inflammatory reaction (IBMIR) following intraportal islet infusion.

Evaluation and Active Treatment versus Active Surveillance of Localized Prostate Cancer in Renal Transplant Patients in the Era of Low and Very Low Risk Prostate Cancer.

PURPOSE: Current trends in renal transplantation, such as improved allograft/recipient survival and expanded organ transplantation eligibility criteria in older recipients, are concomitant with increasingly detected low risk prostate cancer in candidates for or recipients of renal transplantation. We reviewed the evidence regarding prostate cancer screening, diagnosis and management in renal transplant candidates and recipients. We focused on published reports of prostate cancer incidence and diagnosis in patients with end stage renal disease, pretransplant screening recommendations, and recommendations regarding waiting time between treatment and active wait listing after the prostate cancer diagnosis in renal transplant candidates. In addition, we examined the natural history of prostate cancer development after renal transplantation in the setting of standard immunosuppression. MATERIALS AND METHODS: We reviewed the English language literature using search terms including prostate cancer, end stage renal disease, renal transplantation, prostate cancer screening, prostate specific antigen, prostate cancer treatment and active surveillance in various combinations. RESULTS: Prostate cancer screening is still widely done in almost all patients with end stage renal disease before and after transplantation. Active treatment of any patients with prostate cancer and a 5-year waiting period before transplantation can negatively affect the collective pool of participants and the overall survival of patients on dialysis. Several groups have proposed a shorter waiting time to kidney transplantation in patients with low risk prostate cancer. CONCLUSIONS: There are no standardized guidelines for screening and management of prostate cancer before and after transplantation. In the era of low risk prostate cancer end stage renal disease is a significant competing mortality risk factor. The role of active surveillance in these complex cases has yet to be well investigated. Further studies and nomograms are urged to integrate risk stratified screening and treatment protocols before and after renal transplantation.

Application of a Novel CT-Based Iliac Artery Calcification Scoring System for Predicting Renal Transplant Outcomes.

OBJECTIVE: The objective of our study was to assess whether the degree and distribution of iliac artery calcifications as determined by a CT-based calcium scoring system correlates with outcomes after renal transplant. MATERIALS AND METHODS: A retrospective review of renal transplant recipients who underwent CT of the pelvis within 2 years before surgery yielded 131 patients: 75 men and 56 women with a mean age of 52 years. Three radiologists assigned a separate semiquantitative score for calcification length, circumferential involvement, and morphology for the common iliac arteries and for the external iliac arteries. The operative and clinical notes were reviewed to determine which iliac arterial segment was used for anastomosis, the complexity of the operation, and whether delayed graft function (DGF) occurred. Renal allograft survival and patient survival were calculated using the Kaplan-Meier technique. RESULTS: Excellent interobserver agreement was noted for each calcification score category. The common iliac arteries showed significantly higher average calcification scores than the external iliac arteries for all categories. Advanced age and diabetes mellitus were independently predictive of higher scores in each category, whereas hypertension, cigarette smoking, hyperlipidemia, and sex were not. Based on multivariate analysis, only the calcification morphology score of the arterial segment used for anastomosis was independently predictive of a higher rate of surgical complexity and of DGF. None of the scores was predictive of graft or patient survival. However, patients with CT evidence of iliac arterial calcification had a lower 1-year survival after transplant than those who did not (92% vs 98%, respectively; p = 0.05). CONCLUSION: Only the calcification morphology score of the arterial segment used for anastomosis was significantly predictive of surgical complexity and of DGF. Routine pretransplant CT for calcification scoring in patients of advanced age or those with diabetes mellitus may enable selection of the optimal artery for anastomosis to optimize outcomes.

Association of age-dependent liver injury and fibrosis with immune cell populations.

BACKGROUND & AIMS: The liver's response to injury is fibrosis, and when chronic, cirrhosis. Age is a critical factor impacting many immune-mediated processes, potentially including the liver's wounding response to injury. METHODS: The effects of age on acute and chronic liver injury were evaluated using a carbon tetrachloride model in mice. Lymphocyte and macrophage populations were assessed by flow cytometry and immunohistochemical analysis. RESULTS: Acute liver injury was greater in 18-month-old (old) mice than in 9-month-old (middle-aged) mice as judged by changes in aminotransferases. Similarly, livers of 18-month-old mice had a significantly greater fibrogenic response to injury than did livers of 9-month-old mice after chronic injury (assessed by col1α1 mRNA expression, morphometric analysis and hydroxyproline measurement). Interestingly, livers from young mice (6 weeks old) also exhibited an increase in fibrogenesis compared to 9-month-old mice, albeit not to the same degree as in old mice. Consistent with a role for macrophages in fibrogenesis, the number of liver macrophages in young and 9-month-old mice increased, while in chronically injured livers of 18-month-old mice, the number of macrophages was reduced, and was less than in the livers of young and 9-month-old injured livers. CONCLUSIONS: Our data indicate that the fibrogenic response to injury varies substantially with age, and moreover that macrophage recruitment and dynamics may be an important component in differential age-associated fibrotic disease.

Repletion of S-nitrosohemoglobin improves organ function and physiological status in swine after brain death.

OBJECTIVE: To determine if reduction in nitric oxide bioactivity contributes to the physiological instability that occurs after brain death and, if so, to also determine in this setting whether administration of a renitrosylating agent could improve systemic physiological status. BACKGROUND: Organ function after brain death is negatively impacted by reduced perfusion and increased inflammation; the magnitude of these responses can impact post-graft function. Perfusion and inflammation are normally regulated by protein S-nitrosylation but systemic assessments of nitric oxide bioactivity after brain death have not been performed. METHODS: Brain death was induced in instrumented swine by inflation of a balloon catheter placed under the cranium. The subjects were then serially assigned to receive either standard supportive care or care augmented by 20 ppm of the nitrosylating agent, ethyl nitrite, blended into the ventilation circuit. RESULTS: Circulating nitric oxide bioactivity (in the form of S-nitrosohemoglobin) was markedly diminished 10 hours after induction of brain death-a decline that was obviated by administration of ethyl nitrite. Maintenance of S-nitrosohemoglobin was associated with improvements in tissue blood flow and oxygenation, reductions in markers of immune activation and cellular injury, and preservation of organ function. CONCLUSIONS: In humans, the parameters monitored in this study are predictive of post-graft function. As such, maintenance of endocrine nitric oxide bioactivity after brain death may provide a novel means to improve the quality of organs available for donation.

Temporal trends in liver transplant centre volume in the USA.

BACKGROUND: Although prior studies have suggested an inverse association between liver transplant centre volume and postoperative patient mortality, more recent analyses have failed to confirm this association. To date, all studies of the relationship between centre volume and outcomes in liver transplantation have been cross-sectional in design. OBJECTIVE: The objective of our study was to examine temporal trends in the volume-outcomes relationship for liver transplantation. METHODS: We used information obtained from the Scientific Registry of Transplant Recipients (SRTR) programme-specific data reports to examine the outcomes of adult liver transplant recipients stratified by annual centre volume. This relationship between centre volume and patient outcomes was assessed over three consecutive time periods from 2000 through 2007. RESULTS: The overall 25% increase in adult liver transplant volume in the USA from 2000 to 2007 appeared to be distributed fairly equally among existing transplant centres. In the earliest time period of our analysis, high-volume centres achieved superior risk-adjusted 1-year patient outcomes compared with low-volume centres. By the third and most recent time period of the analysis, this discrepancy between the outcomes of high- and low-volume centres was no longer statistically apparent. CONCLUSIONS: The relationship between centre volume and patient outcomes for liver transplantation in the USA has become less pronounced over time, suggesting that the use of procedure volume as a marker of liver transplant centre quality cannot be justified. The performance-based review process currently utilized in the USA may have contributed to this diminishing influence of centre volume on liver transplant recipient outcomes. This type of review process should be considered as a potential alternative to the volume-based referral initiatives that have been developed for other non-transplant, complex surgical procedures.

Relationship between provider volume and outcomes for orthotopic liver transplantation.

INTRODUCTION: Recent data suggests that the previously demonstrable relationship between hospital volume and outcomes for liver transplant procedures may no longer exist. Furthermore, to our knowledge, no study has been published examining whether individual surgeon volume is associated with outcomes in liver transplantation. MATERIALS AND METHODS: The Nationwide Inpatient Sample database was used to obtain early clinical outcome and resource utilization data for liver transplant procedures performed in the USA from 1988 through 2003. The relationship between surgeon and hospital volume and early clinical outcomes was analyzed with and without adjustment for certain confounding variables such as patient age and presence of co-morbid disease. RESULTS: The in-hospital mortality rate, major postoperative complication rate, and length of hospital stay after liver transplantation did not differ significantly based on hospital procedural volume. These outcome variables did, however, exhibit a statistically significant inverse relationship with individual surgeon volume of liver transplant procedures. A significant relationship between procedure volume and outcomes for liver transplantation cannot be demonstrated at the level of transplant center, but does appear to exist at the level of the individual transplant center. CONCLUSION: Minimal volume requirements for individual liver transplant surgeons may be justified, pending validation of this volume-outcomes relationship using a clinical data source.

Temporal trends in early clinical outcomes and health care resource utilization for liver transplantation in the United States.

INTRODUCTION: Procedures such as liver transplantation, which entail large costs while benefiting only a small percentage of the population, are being increasingly scrutinized by third-party payors. The purpose of our study was to conduct a longitudinal analysis of the early clinical outcomes and health care resource utilization for liver transplantation in the United States. METHODS: The Nationwide Inpatient Sample database was used to conduct a longitudinal analysis of the clinical outcome and resource utilization data for liver transplantation procedures in adult recipients performed in the United States over three time periods (Period I: 1988-1993; Period II: 1994-1998: Period III: 1999-2003). RESULTS: Compared to Period I, adult liver transplant recipients were more likely to be male, older, and non-White in Period III. Recipients were more likely to have at least one major comorbidity preoperatively than in Period I. The in-hospital mortality rate after liver transplantation decreased significantly from Period I to Period III, but the major intraoperative and postoperative complication rates increased over the same time period. Mean length of hospital stay decreased over the 15-year period, but the percentage of patients with a non-routine discharge status increased. CONCLUSION: Our findings indicate that the rate of postoperative complications and non-routine discharges after liver transplantation is increasing. However, these negative changes in the cost-outcomes relationship for liver transplantation are balanced by improving postoperative survival rates and reductions in the length of hospital stay.

Half-life analysis of pancreas and kidney transplants.

Although graft and patient survival data are available for pancreas and kidney transplants, they are rarely reported in terms of half-life. Our aim was to determine whether a more relevant measure of outcome is patient and allograft half-life. Using the data from the Organ Procurement and Transplantation Network Registry on kidney and pancreas transplants from January 1988 to December 1996, patient and graft half-life and 95% confidence intervals were calculated and demographic variables compared. No significant differences were found between demographic variables. Kidneys transplanted in diabetics as a simultaneous kidney-pancreas (SPK) fared better than diabetics receiving a kidney alone (9.6 vs. 6.3 years). Pancreatic graft survival in an SPK pair was better than pancreas after kidney transplant or pancreas transplant alone (11.2 vs. 2.5 years). Because kidney and pancreatic grafts have a longer half-life when transplanted with their mate grafts, we should consider the relative benefits of SPKs over pancreas after kidney transplant or pancreas transplant alone to limit the loss of precious resources.

The current status of living donor liver transplantation.

In response to the critical organ shortage, transplant professionals have utilized living donors in an attempt to decrease the mortality rate associated with waiting on the liver transplant list. Although the surgical techniques were first utilized clinically 15 years ago, application of LDLT has been somewhat limited by the steep learning curve associated with developing a program. Clinical success with LDLT in children was realized early in the experience and application of the techniques to the adult population has occurred more recently. Although transplant centers embark on LDLT with enthusiasm, the safety of the donor must always be at the forefront of the process. Potential donors must come to the decision to donate without pressure from members of the family or transplant team. He/she should also be assigned advocates who constantly promote the donor's best interest. Failure to adhere to strict donor evaluation protocols and standardized operative techniques could result in disastrous consequences.

Acute kidney transplant failure following transurethral bladder polyp fulguration.

Ureteral obstruction and anastomotic leak represent the most common urologic complications of kidney transplantation. Delay in diagnosis or treatment can lead to allograft loss. Obstruction of the ureter occurs in 2% of kidney transplant recipients. Although the majority of cases are immediate technical complications of the operation, subsequent manipulation of the genitourinary system can result in iatrogenic ureteral injury. We report the case of a long-term kidney transplant recipient who developed obstructive uropathy and acute renal failure requiring dialysis after undergoing cystoscopy and bladder polyp fulguration. The etiology was inadvertent thermal injury of the ureteroneocystostomy incurred during the procedure. After attempted percutaneous management, definitive open repair resulted in a return of allograft function to baseline.

Gastrointestinal hemorrhage due to complicated gastroduodenal ulcer disease in liver transplant patients taking sirolimus.

Sirolimus is emerging as a popular immunosuppressive agent for patients undergoing solid organ and pancreatic cell transplantation. Here, we report the clinical courses of three patients receiving sirolimus who developed aggressive gastroduodenal ulcer disease. One patient died from massive gastrointestinal bleeding, and ulcers in the other two patients healed only after discontinuation of sirolimus. We propose that the mechanism underlying this severe ulcer diathesis, and poor ulcer healing, was linked to the well-known inhibitory effects of sirolimus on wound healing. We propose that sirolimus should be used carefully (or even withheld) in patients with known or previous ulcer disease, and further that it should be used prudently and/or in conjunction with aggressive prophylaxis therapy in those at risk for ulcer disease.

Intraoperative fluid management during orthotopic liver transplantation.

OBJECTIVE: To assess clinical safety of a low central venous pressure (CVP) fluid management strategy in patients undergoing liver transplantation. DESIGN: Retrospective record review comparing 2 transplant centers, one using the low CVP method and the other using the normal CVP method. SETTING: University-based, academic, tertiary care centers. PARTICIPANTS: Patients undergoing orthotopic cadaveric liver transplantation. INTERVENTIONS: Each center practiced according to its own standard of care. Center 1 maintained an intraoperative CVP <5 mmHg using fluid restriction, nitroglycerin, forced diuresis, and morphine. If pressors were required to maintain systolic arterial pressure >90 mmHg, phenylephrine or norepinephrine was used. At center 2, CVP was kept 7 to 10 mmHg and mean arterial pressure >75 mmHg with minimal use of vasoactive drugs. MEASUREMENTS AND MAIN RESULTS: Data collected included United Network for Organ Sharing status, surgical technique, intraoperative transfusion rate, preoperative and peak postoperative creatinine, time spent in intensive care unit and hospital, incidence of death, and postoperative need for hemodialysis. Principal findings include an increased rate of transfusion in the normal CVP group but increased rates of postoperative renal failure (elevated creatinine and more frequent need for dialysis) and 30-day mortality in the low CVP group. CONCLUSIONS: Despite success in lowering blood transfusion requirements in liver resection patients, a low CVP should be avoided in patients undergoing liver transplantation.