Can remote endarterectomy expand access to kidney transplantation in patients with severe iliac calcification?

Severe iliac artery calcification in patients with end-stage renal disease is a common barrier to listing for kidney transplant. While few surgical solutions to iliac calcification have been reported, improving treatment may thus improve access to transplant care. Here we present two cases of a novel application of remote endarterectomy of the external iliac artery to facilitate listing for renal transplant. Both patients were listed following remote endarterectomy, followed by successful renal transplants using the treated vessels.

Waitlist and Transplant Outcomes in Organ Donation After Circulatory Death: Trends in the United States.

OBJECTIVES: To summarize waitlist and transplant outcomes in kidney, liver, lung, and heart transplantation using organ donation after circulatory death (DCD). BACKGROUND: DCD has expanded the donor pool for solid organ transplantation, most recently for heart transplantation. METHODS: The United Network for Organ Sharing registry was used to identify adult transplant candidates and recipients in the most recent allocation policy eras for kidney, liver, lung, and heart transplantation. Transplant candidates and recipients were grouped by acceptance criteria for DCD versus brain-dead donors [donation after brain death (DBD)] only and DCD versus DBD transplant, respectively. Propensity matching and competing-risks regression was used to model waitlist outcomes. Survival was modeled using propensity matching and Kaplan-Meier and Cox regression analysis. RESULTS: DCD transplant volumes have increased significantly across all organs. Liver candidates listed for DCD organs were more likely to undergo transplantation compared with propensity-matched candidates listed for DBD only, and heart and liver transplant candidates listed for DCD were less likely to experience death or clinical deterioration requiring waitlist inactivation. Propensity-matched DCD recipients demonstrated an increased mortality risk up to 5 years after liver and kidney transplantation and up to 3 years after lung transplantation compared with DBD. There was no difference in 1-year mortality between DCD and DBD heart transplantation. CONCLUSIONS: DCD continues to expand access to transplantation and improves waitlist outcomes for liver and heart transplant candidates. Despite an increased risk for mortality with DCD kidney, liver, and lung transplantation, survival with DCD transplant remains acceptable.

Multicenter study of racial and ethnic inequities in liver transplantation evaluation: Understanding mechanisms and identifying solutions.

Racial and ethnic disparities persist in access to the liver transplantation (LT) waiting list; however, there is limited knowledge about underlying system-level factors that may be responsible for these disparities. Given the complex nature of LT candidate evaluation, a human factors and systems engineering approach may provide insights. We recruited participants from the LT teams (coordinators, advanced practice providers, physicians, social workers, dieticians, pharmacists, leadership) at two major LT centers. From December 2020 to July 2021, we performed ethnographic observations (participant-patient appointments, committee meetings) and semistructured interviews (N = 54 interviews, 49 observation hours). Based on findings from this multicenter, multimethod qualitative study combined with the Systems Engineering Initiative for Patient Safety 2.0 (a human factors and systems engineering model for health care), we created a conceptual framework describing how transplant work system characteristics and other external factors may improve equity in the LT evaluation process. Participant perceptions about listing disparities described external factors (e.g., structural racism, ambiguous national guidelines, national quality metrics) that permeate the LT evaluation process. Mechanisms identified included minimal transplant team diversity, implicit bias, and interpersonal racism. A lack of resources was a common theme, such as social workers, transportation assistance, non-English-language materials, and time (e.g., more time for education for patients with health literacy concerns). Because of the minimal data collection or center feedback about disparities, participants felt uncomfortable with and unadaptable to unwanted outcomes, which perpetuate disparities. We proposed transplant center-level solutions (i.e., including but not limited to training of staff on health equity) to modifiable barriers in the clinical work system that could help patient navigation, reduce disparities, and improve access to care. Our findings call for an urgent need for transplant centers, national societies, and policy makers to focus efforts on improving equity (tailored, patient-centered resources) using the science of human factors and systems engineering.

Successful Implementation of Unmanned Aircraft Use for Delivery of a Human Organ for Transplantation.

OBJECTIVE: To understand and overcome the challenges associated with moving life-urgent payloads using unmanned aircraft. BACKGROUND DATA: Organ transportation has not been substantially innovated in the last 60 years. Unmanned aircraft systems (UAS; ie, drones) have the potential to reduce system inefficiencies and improve access to transplantation. We sought to determine if UASs could successfully be integrated into the current system of organ delivery. METHODS: A multi-disciplinary team was convened to design and build an unmanned aircraft to autonomously carry a human organ. A kidney transplant recipient was enrolled to receive a drone-shipped kidney. RESULTS: A uniquely designed organ drone was built. The aircraft was flown 44 times (total of 7.38 hours). Three experimental missions were then flown in Baltimore City over 2.8 miles. For mission #1, no payload was carried. In mission #2, a payload of ice, saline, and blood tubes (3.8 kg, 8.4 lbs) was flown. In mission #3, a human kidney for transplant (4.4 kg, 9.7 lbs) was successfully flown by a UAS. The organ was transplanted into a 44-year-old female with a history of hypertensive nephrosclerosis and anuria on dialysis for 8 years. Between postoperative days (POD) 1 and 4, urine increased from 1.0 L to 3.6 L. Creatinine decreased starting on POD 3, to an inpatient nadir of 6.9 mg/dL. The patient was discharged on POD 4. CONCLUSIONS: Here, we completed the first successful delivery of a human organ using unmanned aircraft. This study brought together multidisciplinary resources to develop, build, and test the first organ drone system, through which we performed the first transplant of a drone transported kidney. These innovations could inform not just transplantation, but other areas of medicine requiring life-saving payload delivery as well.

G-CSF promotes alloregulatory function of MDSCs through a c-Kit dependent mechanism.

Myeloid-derived suppressor cells (MDSC) are a heterogeneous population of immature myeloid cells that expand in inflammatory conditions including transplantation. MDSCs may be capable of controlling rejection. The critical mechanisms underlying MDSC mediated alloregulation remain unexplored. G-CSF potently stimulates MDSC expansion. We hypothesized that G-CSF-induced MDSCs use a novel mechanism to suppress T cell responses. G-CSF promoted expansion of MDSCs and enhanced their suppressive function against T cell proliferation. Gene expression analysis revealed MDSCs expanded with G-CSF upregulated immune-related genes, but downregulated proliferation-related genes when compared to naïve control MDSCs. The KIT oncogene, encoding the c-Kit (CD117) transmembrane tyrosine kinase receptor, was the most significantly increased in MDSCs expanded with G-CSF. c-Kit inhibition with both imatinib and monoclonal blocking antibody reduced expression of ARG-1, iNOS, PD-L1, and SAA3. Further, imatinib also reduced MDSC-mediated T cell suppression in vitro. Modulation of c-Kit activity may represent a therapeutic target for alloregulatory MDSCs.

Myeloid-derived suppressor cells expand after transplantation and their augmentation increases graft survival.

Myeloid-derived suppressor cells (MDSCs) expand in an inflammatory microenvironment such as cancer and autoimmunity. To study if transplantation induces MDSCs and these cells regulate allograft survival, C57BL/6 donor hearts were transplanted into BALB/c recipients and endogenous MDSCs were characterized. The effects of adoptive transfer of transplant (tx), tumor (tm), and granulocyte-colony stimulating factor (g-csf)-expanded MDSCs or depletion of MDSC were assessed. MDSCs expanded after transplantation (1.7-4.6-fold) in the absence of immunosuppression, homed to allografts, and suppressed proliferation of CD4 T cells in vitro. Tx-MDSCs differed phenotypically from tm-MDSCs and g-csf-MDSCs. Among various surface markers, Rae-1 expression was notably low and TGF-ß receptor II was high in tx-MDSCs when compared to tm-MDSCs and g-csf-MDSCs. Adoptive transfer of these three MDSCs led to differential graft survival: control (6 days), tx-MDSCs (7.5 days), tm-MDSCs (9.5 days), and g-csf-MDSCs (19.5 days). In combination with anti-CD154 mAb, MDSCs synergistically extended graft survival from 40 days (anti-CD154 alone) to 86 days with tm-MDSCs and 132 days with g-csf-MDSCs. Early MDSC depletion (day 0 or 20), however, abrogated graft survival, but late depletion (day 25) did not. In conclusion, MDSCs expanded following transplantation, migrated to cardiac allografts, prolonged graft survival, and were synergistic with anti-CD154 mAb.

Panniculectomy at the time of living donor renal transplantation: An 8-year experience.

Panniculectomy can be performed as a prophylactic procedure preceding transplantation to enable obese patients to meet criteria for renal transplantation. No literature exists on combined renal transplant and panniculectomy surgery (LRT-PAN). We describe our 8-year experience performing LRT-PAN. A retrospective chart review of all patients who had undergone LRT-PAN from 2010 to 2018 was conducted. Data were collected on patient demographics, allograft survival and function, and postoperative course. Fifty-eight patients underwent LRT-PAN. All grafts survived, with acceptable function at 1 year. Median length of stay was 4 days with a mean operative duration of 363 minutes. The wound complication rate was 24%. Ninety-day readmission rate was 52%, with medical causes as the most common reason for readmission (45%), followed by wound (32%) and graft-related complications (23%). Body mass index, diabetes status, and previous immunosuppression did not influence wound complication rate or readmission (P = .7720, P = .0818, and P = .4830, respectively). Combining living donor renal transplant and panniculectomy using a multidisciplinary team may improve access to transplantation, particularly for the obese and postobese population. This combined approach yielded shorter-than-expected hospital stays and similar wound complication rates, and thus should be considered for patients in whom transplantation might otherwise be withheld on the basis of obesity.

Harms of unsuccessful donation after circulatory death: An exploratory study.

While donation after circulatory death (DCD) has expanded options for organ donation, many who wish to donate are still unable to do so. We conducted face-to-face interviews with family members (N = 15) who had direct experience with unsuccessful DCD and 5 focus groups with professionals involved in the donation process. We used qualitative content analysis to characterize the harms of nondonation as perceived by participants. Participants reported a broad spectrum of harms affecting organ recipients, donors, and donor families. Harms included waste of precious life-giving organs and hospital resources, inability to honor the donor's memory and character, and impaired ability for families to make sense of tragedy and cope with loss. Donor families empathized with the initial hope and ultimate despair of potential recipients who must continue their wait on the transplant list. Focus group members reinforced these findings and highlighted the struggle of families to navigate the uncertainty regarding the timing of death during the donation process. While families reported significant harm, many appreciated the donation attempt. These findings highlight the importance of organ donation to donor families and the difficult experiences associated with current processes that could inform development of alternative donation strategies.

Diabetic nephropathy after kidney transplantation in patients with pretransplantation type II diabetes: A retrospective case series study from a high-volume center in the United States.

BACKGROUND: Patients with type II diabetes mellitus (DM) undergoing renal transplantation are at risk of diabetic nephropathy (DN) in the transplanted kidney. The true risk of developing post-transplantation DN is unknown, and post-transplantation DN is poorly characterized in the literature. METHODS: The biopsy database at the University of Maryland Medical Center was queried for kidney transplant biopsies which demonstrated evidence of DN. The time from transplantation to biopsy-proven DN (time to diagnosis, TTD) was calculated and analyzed in the context of demographics, serum creatinine, and onset of diabetes. By extrapolating the total number of patients who developed DN in the last 2 years, we estimated the recurrence rate of DN. RESULTS: Sixty patients whose renal biopsies met criteria were identified. The mean age was 56.6 (±1.58) years, and the mean creatinine level at time of biopsy was 1.65 (±0.12) mg/dL. Simultaneous pathological diagnoses were frequent on kidney biopsy; rejection was present at variable rates: classes I, IIA, IIB, and III were 5.0%, 66.7%, 18.4%, and 10%, respectively. The mean TTD was 1456 (±206) days. TTD was significantly shorter for patients receiving a cadaveric vs living donor renal transplant (1118 ± 184 vs 2470 ± 547 days, P = 0.004). Older patients (r = 0.378, P = 0.003) and patients with higher serum creatinine (r = 0.282, P = 0.029) had shorter TTDs. Extrapolations showed that 74.7% of patients would be free of DN 10 years after renal transplantation. CONCLUSIONS: Diabetic nephropathy occurs after transplantation, and this appears to be due to both donor and recipient-derived factors. Encouragingly, our estimates suggest that as many as 75% of patients may be free of DN at 10 years following kidney transplantation.

Successful pancreas transplantation alone is associated with excellent self-identified health score and glucose control: A retrospective study from a high-volume center in the United States.

BACKGROUND: The benefits of pancreas transplantation are often difficult to measure. Here, we sought to determine the difference in quality of life for diabetic patients with and without a functional pancreas transplant alone (PTA). METHODS: Pancreas transplant alone cases from 1993 to 2015 were considered. An IRB-approved survey inclusive of 15 questions spanning four domains was employed. Chi-square, Fisher's exact, and the T test were used where appropriate. RESULTS: A total of 137 PTAs were performed during the study period. Of those reached (n = 32), 94% responded to the survey. Self-reported health scores were better (2.1 vs 3.0) for those with functioning pancreata (n = 18) vs those with a non-functional pancreas (n = 14), respectively (P = .036). Those with a functional pancreas had a HgbA1c of 5.3, vs 7.7 for a non-functional pancreas (P = .016). Significant hypoglycemia was reported in two of 18 with a functional transplant vs nine of 14 patients with a failed transplant (P = .003). Daily frustration with blood sugar affecting quality of life was significantly higher for patients with non-functional pancreas grafts (P < .001). CONCLUSIONS: Pancreas transplantation alone is associated with better glucose control than insulin. In addition, recipients of functional PTAs have improved quality of life and better overall health scores than those with failed grafts.

Molecular Adsorbent Recirculating System Effectively Replaces Hepatic Function in Severe Acute Liver Failure.

BACKGROUND DATA: Patients with severe acute liver failure (ALF) have extreme physiologic dysfunction and often die if transplantation is not immediately available. Patients may be supported with MARS (Baxter International Inc., Deerfield, IL) until transplantation or spontaneous recovery occurs. We present the largest series in the United States of MARS therapy as temporary hepatic replacement for ALF. METHODS: MARS was used to support patients with severe liver trauma (SLT), in ALF patients as a bridge to transplantation (BTT), and as definitive therapy for toxic ingestion or idiopathic liver failure (DT) in a level 1 trauma center and large transplant center. Patient demographics, etiology of ALF, and laboratory values were recorded. Endpoints were patient survival ± liver transplant and/or recovery of liver function. RESULTS: Twenty-seven patients with severe ALF received MARS therapy. Five patients with SLT had a 60% survival with recovery of liver and renal function. Thirteen patients received MARS as a BTT, of which 9 were transplanted with a 1-year survival of 78% (program overall survival 85% at 1 year). All 4 who were not transplanted expired. Nine patients with ALF from toxic ingestion received MARS as DT with liver recovery and survival in 67%. MARS therapy resulted in significant improvement in liver function, coagulation, incidence of encephalopathy, and creatinine. CONCLUSIONS: MARS therapy successfully replaced hepatic function in ALF allowing time for spontaneous recovery or transplantation. Spontaneous recovery was remarkably common if support can be sustained.

An overview of the necessary thymic contributions to tolerance in transplantation.

The thymus is important for the development of the immune system. However, aging leads to predictable involution of the thymus and immunodeficiency. These immunodeficiencies may be rectified with thymic rejuvenation. Atrophy of the thymus is governed by a complex interplay of molecular, cytokine and hormonal factors. Herein we review the interaction of these factors across age and how they may be targeted for thymic rejuvenation. We further discuss the growing pre-clinical evidence defining the necessary and sufficient contributions of the thymus to successful tolerance induction in transplantation.

When Do DCD Donors Die?: Outcomes and Implications of DCD at a High-volume, Single-center OPO in the United States.

OBJECTIVE: The objective of this study was to determine the fate of patients who attempted to donate organs after circulatory death (DCD) using a standardized DCD protocol. BACKGROUND: Successful donation is not always possible after attempted DCD. METHODS: Data were collected for all DCD donors between 1/2011 and 9/2014. DCDs were carried out using a uniform protocol at a single-center organ procurement organization. RESULTS: During the timeframe considered, DCD donation was attempted in 169 patients. In 46 patients (27.2%), no organs were recovered because the patients did not die within 2 hours. Successful donation was more likely if withdrawal of support occurred in the operating room versus the intensive care unit (P = 0.006). Time from extubation to death was available for 161/169 donors (95.3%). Of 161 donors, 111 (66.9%) died in under 1 hour. The mean time from withdrawal of support to patient death for unsuccessful donations was 33 hours, 37 minutes (range, 24 minutes-242 hours) versus 29 minutes (range, 5 minutes-2 hours, 4 minutes) for successful donations. Twenty-seven patients who unsuccessfully donated (67.5%) died within 24 hours. Were unsuccessful donations converted to successful donations, as many as 837 abdominal transplants could have been carried out in the United States, during the study period. CONCLUSIONS: DCD is an important form of organ donation. A large number of abdominal transplants are not possible due to unsuccessful DCD organ donation. It may be useful to explore DCD donor family satisfaction to identify other options for improving DCD donation.

Liver transplant outcomes using ideal donation after circulatory death livers are superior to using older donation after brain death donor livers.

Multiple reports have demonstrated that liver transplantation following donation after circulatory death (DCD) is associated with poorer outcomes when compared with liver transplantation from donation after brain death (DBD) donors. We hypothesized that carefully selected, underutilized DCD livers recovered from younger donors have excellent outcomes. We performed a retrospective study of the United Network for Organ Sharing database to determine graft survivals for patients who received liver transplants from DBD donors of age ≥ 60 years, DBD donors < 60 years, and DCD donors < 50 years of age. Between January 2002 and December 2014, 52,271 liver transplants were performed in the United States. Of these, 41,181 (78.8%) underwent transplantation with livers from DBD donors of age < 60 years, 8905 (17.0%) from DBD donors ≥ 60 years old, and 2195 (4.2%) livers from DCD donors < 50 years of age. DCD livers of age < 50 years with < 6 hours of cold ischemia time (CIT) had superior graft survival when compared with DBD livers ≥ age 60 years (P < 0.001). In 2014, there were 133 discarded DCD livers; of these, 111 (83.4%) were from donors < age 50 years old. Young DCD donor livers (age < 50 years old) with short CITs yield results better than that seen with DBD livers > 60 years old. Careful donor organ and recipient selection can lead to excellent results, despite previous reports suggesting otherwise. Increased acceptance of these DCD livers would lead to shorter wait list times and increased national liver transplant rates. Liver Transplantation 22 1197-1204 2016 AASLD.

The mode of sensitization and its influence on allograft outcomes in highly sensitized kidney transplant recipients.

BACKGROUND: We sought to determine whether the mode of sensitization in highly sensitized patients contributed to kidney allograft survival. METHODS: An analysis of the United Network for Organ Sharing dataset involving all kidney transplants between 1997 and 2014 was undertaken. Highly sensitized adult kidney transplant recipients [panel reactive antibody (PRA) ≥98%] were compared with adult, primary non-sensitized and re-transplant recipients. Kaplan-Meier survival analyses were used to determine allograft survival rates. Cox proportional hazards regression analyses were conducted to determine the association of graft loss with key predictors. RESULTS: Fifty-three percent of highly sensitized patients transplanted were re-transplants. Pregnancy and transfusion were the only sensitizing event in 20 and 5%, respectively. The 10-year actuarial graft survival for highly sensitized recipients was 43.9% compared with 52.4% for non-sensitized patients, P < 0.001. The combination of being highly sensitized by either pregnancy or blood transfusion increased the risk of graft loss by 23% [hazard ratio (HR) 1.230, confidence interval (CI) 1.150-1.315, P < 0.001], and the combination of being highly sensitized from a prior transplant increased the risk of graft loss by 58.1% (HR 1.581, CI 1.473-1.698, P < 0.001). CONCLUSIONS: The mode of sensitization predicts graft survival in highly sensitized kidney transplant recipients (PRA ≥98%). Patients who are highly sensitized from re-transplants have inferior graft survival compared with patients who are highly sensitized from other modes of sensitization.

Predictors and outcomes of delayed graft function after living-donor kidney transplantation.

Delayed graft function (DGF) following deceased donor kidney transplantation is associated with inferior outcomes. Delayed graft function following living-donor kidney transplantation is less common, but its impact on graft survival unknown. We therefore sought to determine risk factors for DGF following living-donor kidney transplantation and DGF's effect on living-donor kidney graft survival. We analyzed living-donor kidney transplants performed between 2000 and 2014 in the UNOS dataset. A total of 64 024 living-donor kidney transplant recipients were identified, 3.6% developed DGF. Cold ischemic time, human leukocyte antigen mismatch, donor age, panel reactive antibody, recipient diabetes, donor and recipient body mass index, recipient race and gender, right nephrectomy, open nephrectomy, dialysis status, ABO incompatibility, and previous transplants were independent predictors of DGF in living-donor kidney transplants. Five-year graft survival among living-donor kidney transplant recipients with DGF was significantly lower compared with graft survival in those without DGF (65% and 85%, respectively, P < 0.001). DGF more than doubled the risk of subsequent graft failure (hazard ratio = 2.3, 95% confidence interval: 2.1-2.6; P < 0.001). DGF after living-donor kidney transplantation is associated with inferior allograft outcomes. Minimizing modifiable risk factors may improve outcomes in living-donor kidney transplantation.

Pancreas transplantation in older patients is safe, but patient selection is paramount.

Pancreas transplant outcomes have progressively improved. Despite this, some centers have continued to employ historical age limits for pancreas transplant candidates. We sought to determine the importance of chronological age in determining patient and graft survival rates after pancreas transplantation. A single-center, retrospective study of adult, deceased donor simultaneous pancreas and kidney (SPK) and solitary pancreas transplants (SP, including pancreas transplant alone and pancreas after kidney transplants) in recipients ≥ 55 years (55 + ), occurring between July 1, 1999, and June 30, 2012, was performed. Seven-hundred and forty patients underwent pancreas transplantation, of which 28 patients were 55 + . Patient survival was comparable for younger and older pancreas transplant recipients. Both non-death-censored and death-censored pancreatic graft survival rates were similar in younger and in older patients. Patients aged 45-54 and those aged 55 +  had more frequent cardiovascular events than younger pancreas transplant recipients. There was no difference in renal graft survival for SPK patients when compared with diabetic kidney transplant alone recipients aged 55 years and older. Older pancreas transplant recipients had acceptable long-term patient and graft survival rates, although complications may occur. Chronological age alone should not exclude a patient for pancreas transplant candidacy.

Older kidney transplant patients experience less antibody-mediated rejection: a retrospective study of patients with mild to moderate sensitization.

BACKGROUND: There is a paucity of data stratifying by age the incidence of antibody-mediated rejection (AMR) in kidney transplant patients. METHODS: We performed a retrospective study of all adult, renal transplant recipients at a single institution between December 12, 2009, and March 16, 2011. Mildly and moderately sensitized patients were defined as patients with positive donor-specific antibody (DSA) and negative flow cross-match. RESULTS: One hundred and forty-six patients were determined to have mild to moderate pre-transplantation sensitization. Thirty percent of patients younger than 40 yr of age experienced AMR vs. 15% in the older group (p = 0.04). There was a disproportionate increase in DSA for younger patients at 12 months, particularly for antibodies to class II. Histologic presence of C4d deposition was independently associated with AMR on multivariate analysis. CONCLUSIONS: Following renal transplantation, moderately sensitized patients aged 40 yr old and older were less likely to develop AMR when compared with younger patients.

Simultaneous pancreas and kidney transplantation: current trends and future directions.

PURPOSE OF REVIEW: Important trends are being observed in pancreas transplantation in the USA. We will describe recent trends in simultaneous pancreas kidney (SPK) transplantation related to immunosuppression, treatment of rejection, and transplantation for patients of advanced age and C-peptide positive diabetes. RECENT FINDINGS: Rates of pancreas transplantation have declined, despite improved pancreatic graft outcomes. Regarding immunosuppression, trends in SPK transplantation include T-cell depletion induction therapy, waning mammalian target of rapamycin inhibitor use and steroid use in greater than 50% of pancreas transplant recipients with few patients undergoing late steroid weaning. Rejection of the pancreas may be discordant with the kidney after SPK and there is a greater appreciation of antibody-mediated rejection of the pancreas allograft. De-novo donor-specific antibody without graft dysfunction remains an active area of study, and the treatment for this condition is unclear. SPKs are being performed with greater frequency in type 2 diabetes mellitus patients and in patients of advanced age, with exemplary results. SUMMARY: The current state of the art in SPK transplantation is yielding superb and improving results.