Successful Opioid Minimization Following Kidney Transplant: A Quality Improvement Initiative.

Opioid use after kidney transplant has been associated with an increased risk of death and graft loss. Several transplant centers have reported reductions in opioid use using multimodal analgesia and education. This study evaluated the impact of an opioid minimization protocol on inpatient opioid use and opioid prescribing on discharge. This was a single-center, retrospective study of adult kidney recipients transplanted from October 2021 to July 2022. Patients on chronic opioids prior to transplant were excluded. The protocol included an intra-operative ultrasound-guided lateral transversus abdominis plane (TAP) block combined with scheduled non-opioid analgesics and tramadol as needed. Acetaminophen 1000 mg and gabapentin 300 mg were given 1 hour prior to the procedure and continued three times daily after transplant. The gabapentin dose was reduced for patients with renal impairment. Additional analgesics including opioids could be added for uncontrolled pain. We hypothesized the protocol would decrease total inpatient morphine milligram equivalents (MMEs) and opioid prescribing on discharge. Fifty-nine post-protocol patients were compared to 52 pre-protocol patients. After the protocol, there was a significant decrease in total inpatient MMEs per day administered and no patient-controlled analgesia (PCA) devices were required. In alignment with the protocol, there was a significant increase in the use of TAP blocks, acetaminophen, gabapentin, and lidocaine patches. While opioid use was lowest in post-protocol patients who received TAP blocks, significant reductions in MMEs per day were still seen in those post-protocol who did not receive TAP blocks. Opioid prescribing at the time of discharge decreased significantly after protocol. No difference was seen in patient-reported pain scores, return to operating room, readmission within 30 days, or length of stay. The use of scheduled acetaminophen and gabapentin with or without a TAP block allowed the elimination of PCA devices and led to significant minimizations in both inpatient opioid use and opioid prescribing on discharge.

Long-term outcomes after COVID-19 infection in transplant recipients.

BACKGROUND: Long-term outcomes after COVID-19 infection unique to solid organ transplant recipients (SOTR) are not published. We describe outcomes including readmission, allograft rejection, allograft dysfunction, allograft failure, and death. METHODS: We conducted a retrospective cohort study of mostly unvaccinated SOTR with COVID-19 from March 2020 to November 2021. Disease severity was assigned by NIH criteria. Data included demographics, clinical features, treatment, and outcomes and are presented as mean ± standard deviation or median (range). RESULTS: One hundred and thirty-eight SOTR were diagnosed with COVID-19 at a median of 5 (IQR 3-8) years post-transplant with a mean age of 57 ± 12 years at diagnosis. Forty-one recovered at home; 97 were admitted. 12/32 (37.5%) SOTR with critical disease expired during initial admission. Among those who recovered, 48/126 (38.0%) had asymptomatic or mild infection, 31/126 (24.6%) had moderate, 27/126 (21.4%) severe, and 20/126 (15.9%) critical infection. 38/85 (44.7%) of SOTR who survived initial admission had 74 readmissions within 180 days (Figure 1). The 6-month mortality rate among those who survived infection was 4/126 (3.2%). The mean time from initial infection to death was 32 ± 66 days in inpatient deaths and 95 ± 39 days in those who were discharged or never admitted. Six-month graft dysfunction occurred in 18/125 (14.4%) and graft failure in 9/126 (7.2%); five failures were deaths with function. CONCLUSION: Readmissions after COVID-19 infection were frequent after the index admission. Rejection was relatively infrequent; graft dysfunction at 6 months post-infection was more common than rejection. Six-month mortality following COVID-19 recovery in SOTR was significant; close follow-up of patients is warranted.

Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.

Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine.

Objectives: Solid organ transplant recipients (SOTR) receiving post-transplant immunosuppression show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. Methods: We analysed humoral immune responses against SARS-CoV-2 and its variants in 53 SOTR receiving SARS-CoV-2 vaccination. Results: Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4+ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants. Conclusion: Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron where antibody responses and neutralising activity remained suboptimal.

Arguments against the Requirement of a Biological License Application for Human Pancreatic Islets: The Position Statement of the Islets for US Collaborative Presented during the FDA Advisory Committee Meeting.

The Food and Drug Administration (FDA) has been regulating human islets for allotransplantation as a biologic drug in the US. Consequently, the requirement of a biological license application (BLA) approval before clinical use of islet transplantation as a standard of care procedure has stalled the development of the field for the last 20 years. Herein, we provide our commentary to the multiple FDA's position papers and guidance for industry arguing that BLA requirement has been inappropriately applied to allogeneic islets, which was delivered to the FDA Cellular, Tissue and Gene Therapies Advisory Committee on 15 April 2021. We provided evidence that BLA requirement and drug related regulations are inadequate in reassuring islet product quality and potency as well as patient safety and clinical outcomes. As leaders in the field of transplantation and endocrinology under the "Islets for US Collaborative" designation, we examined the current regulatory status of islet transplantation in the US and identified several anticipated negative consequences of the BLA approval. In our commentary we also offer an alternative pathway for islet transplantation under the regulatory framework for organ transplantation, which would address deficiencies of in current system.

Post-Abdominal Transplant Hernia: Can We Predict Size and Onset?

INTRODUCTION: Abdominal organ transplant is a life-saving treatment. However, the resultant weakening of abdominal muscles leaves patients susceptible to incisional hernia. Obesity, smoking, and diabetes mellitus are common risk factors for post-transplant hernia. However, the literature is void on the impact these risk factors have on timing and size of hernia. METHODS: We performed a retrospective review of all post-abdominal transplant patients who underwent hernia repair in 2010-2017 at a single institution. Primary outcomes were hernia size and time from transplant to hernia repair. RESULTS: We identified 31 patients. The majority of patients were female (15 male, 16 female), and the average patient was 56 ± 8.7 years old and obese (body mass index 30.6). Smoking (26.7%, n = 8) and diabetes mellitus (51.6%, n = 16) were prevalent. Transplant types represented were renal (n = 24), simultaneous pancreas-kidney (n = 5), liver (n = 1), and liver with subsequent kidney (n = 1). The median size of hernia was 100.0 cm2 (interquartile range [IQR]: 78.5-234.0), and median time to hernia repair was 53.0 months (IQR: 12.5-110.0). Risk factors (obesity, smoking, and diabetes) did not influence hernia size, nor alter time to hernia repair. CONCLUSION: Obesity, smoking, and diabetes mellitus are not prognostic of size or onset of post-transplant incisional hernia. Large cohort studies are needed to determine predictive factors of size and onset of hernia.

The demise of islet allotransplantation in the United States: A call for an urgent regulatory update.

Islet allotransplantation in the United States (US) is facing an imminent demise. Despite nearly three decades of progress in the field, an archaic regulatory framework has stymied US clinical practice. Current regulations do not reflect the state-of-the-art in clinical or technical practices. In the US, islets are considered biologic drugs and "more than minimally manipulated" human cell and tissue products (HCT/Ps). In contrast, across the world, human islets are appropriately defined as "minimally manipulated tissue" and not regulated as a drug, which has led to islet allotransplantation (allo-ITx) becoming a standard-of-care procedure for selected patients with type 1 diabetes mellitus. This regulatory distinction impedes patient access to islets for transplantation in the US. As a result only 11 patients underwent allo-ITx in the US between 2016 and 2019, and all as investigational procedures in the settings of a clinical trials. Herein, we describe the current regulations pertaining to islet transplantation in the United States. We explore the progress which has been made in the field and demonstrate why the regulatory framework must be updated to both better reflect our current clinical practice and to deal with upcoming challenges. We propose specific updates to current regulations which are required for the renaissance of ethical, safe, effective, and affordable allo-ITx in the United States.

A Multidisciplinary Technique for Concurrent Panniculectomy-Living Donor Renal Transplantation.

BACKGROUND: Recently, it has been shown that panniculectomy concurrent to living donor renal transplantation is a safe option for management of renal transplant recipients with a large focal pannus. This combined management requires precise coordination of teams. We describe the technique, timing, and sequence for combined renal transplantation and panniculectomy. METHODS: We conducted a retrospective chart review of adult patients (≥18 years old) who underwent simultaneous living donor renal transplantation-panniculectomy from 2015 to 2019. A multi-team approach that included urology, transplant, and plastic surgery was used to perform the combined operations. Typically, the plastic surgery team initiates the operation by performing the panniculectomy. This is followed by kidney transplantation and graft anastomosis. The plastic surgery team then completes the operation with closure of the wound. RESULTS: Twenty patients were identified. Most were male (12:8) with a mean age of 55 years and an average body mass index of 35 kg/m. The mean total operative duration was 394 minutes. On average, 17% of operating time was devoted to panniculectomy. At 90 days follow-up, there was 100% graft survival and all patients had primary graft function. There was a 25% wound complications rate and a 15% reoperation rate. CONCLUSION: By performing panniculectomy first in the sequence, concurrent panniculectomy provides wide exposure and a large operative field for transplantation. Wound closure by plastic surgeons may mitigate the high complication rate commonly seen in obese patients with end-stage renal disease. Future studies are needed to evaluate the cost-benefit of the combined living donor renal transplantation-panniculectomy.

Teamwork Makes the Dream Work: Maximizing Surgical Intervention at the Time of Living Donor Renal Transplantation.

BACKGROUND: Patients with obesity and end-stage renal disease represent a surgical population with multiple comorbidities and high risk for postoperative complications. One method for reducing the incidence of postoperative adverse events in this patient population is to limit the number of operations through combining operations into 1 operative encounter. METHODS: We conducted a retrospective review of adult patients at a single institution who underwent renal transplant, panniculectomy, and at least 1 additional abdominal or pelvic surgery concurrently. For those patients, we collected demographics, intraoperative variables, and postoperative data and analyzed surgical outcomes and postoperative complications. RESULTS: Thirteen patients met inclusion criteria. Most of the patients were female (85%) with ages ranging 33 to 70 years old and mean body mass index of 36.5 (SD 4.7). Three quarters of patients (77%) underwent 3 procedures and the remaining underwent 4 or 5 procedures with a median hospital length of stay of 5 days (range, 3-10 days). There was a single mortality. Overall, 8 patients (61.5%) experienced complications in the first 90 postoperative days. The wound complication rate was 46.2%, the overall readmission rate within 90 days was 38.5%, and the reoperation rate was 30.8%. All patients experienced immediate graft function, and the 12 patients that survived to postoperative day 90 maintained survival at 1 year. CONCLUSION: This study demonstrates that the combination of more than 2 surgical procedures with living donor renal transplant is a possible treatment option in high-risk obese patients in need of multiple operations.

Geographic Disparities in Access to Simultaneous Pancreas and Kidney Transplant in the Pre- and Post-Pancreas Allocation System Eras.

BACKGROUND: The 2014 pancreas allocation system (PAS) intended to decrease geographic variability in listing practices for simultaneous pancreas and kidney (SPK) transplant and define eligibility criteria for those with type 2 diabetes mellitus (T2DM). Our primary aims were to evaluate geographic disparities in access to SPK and assess T2DM SPK listings in the pre- and post-PAS eras. METHODS: Adult listings for SPK and kidney transplant (pre-PAS, January 2010 to October 29, 2014; post-PAS, October 30, 2014, to June 2, 2017) were identified in the Scientific Registry of Transplant Recipients. Multivariable logistic regression models tested associations of geography and/or diabetes mellitus type on the likelihood of SPK versus kidney transplant listing pre- and post-PAS. Competing risk models tested the likelihood of SPK transplantation within 2 years of listing for SPK. RESULTS: Among 41 205 listings (27 393 pre-PAS; 24 439 T2DM), univariate analysis showed reduced percentages for SPK post-PAS (22.1%-20.8%; P = 0.003). After adjusting for patient and center characteristics, geographic disparities declined slightly but persisted post-PAS (era by region interaction P < 0.001). The era by type of diabetes mellitus interaction effect was statistically significant (P = 0.039), reflecting that the proportions of SPK listings for T2DM increased in the post-PAS era (3.4%-3.9%; univariate P = 0.038), while those for type 1 diabetes mellitus remained statistically stable (47.9%-48.4%; univariate P = 0.571). Among people listed for SPK, geographic disparities in the cumulative incidence of transplantation within 2 years declined and the overall likelihood of transplantation increased in the post-PAS era (both P < 0.001). CONCLUSIONS: Geographic disparities in access to SPK declined slightly but persisted post-PAS. With new allocation change proposals and elimination of listing criteria for T2DM, further monitoring is warranted.

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.

C-peptide levels do not correlate with pancreas allograft failure: Multicenter retrospective analysis and discussion of the new OPT definition of pancreas allograft failure.

The OPTN Pancreas Transplantation Committee performed a multicenter retrospective study to determine if undetectable serum C-peptide levels correspond to center-reported pancreas graft failures. C-peptide data from seven participating centers (n = 415 graft failures for transplants performed from 2002 to 2012) were analyzed pretransplant, at graft failure, and at return to insulin. One hundred forty-nine C-peptide values were submitted at pretransplant, 94 at return to insulin, and 233 at graft failure. There were 77 transplants with two available values (at pretransplant and at graft failure). For recipients in the study with pretransplant C-peptide <0.75 ng/mL who had a posttransplant C-peptide value available (n = 61), graft failure was declared at varying levels of C-peptide. High C-peptide values at graft failure were not explained by nonfasting testing or by individual center bias. Transplant centers declare pancreas graft failure at varying levels of C-peptide and do not consistently report C-peptide data. Until February 28, 2018, OPTN did not require reporting of posttransplant C-peptide levels and it appears that C-peptide levels are not consistently used for evaluating graft function. C-peptide levels should not be used as the sole criterion for the definition of pancreas graft failure.

The survival advantage of pancreas after kidney transplant.

Patient survival after pancreas after kidney transplant (PAK) has been reported to be inferior to patient survival after simultaneous pancreas-kidney transplant (SPK). The authors examine national data to further explore allograft (kidney and pancreas) and patient survival after PAK. Kaplan-Meier and Cox proportional hazard models were used to analyze Organ Procurement and Transplantation Network data from 1995 to 2010. The analysis compared PAK and SPK candidates and recipients. Kaplan-Meier analysis results showed that PAK after either a living or a deceased donor kidney transplant is associated with increased kidney graft survival compared with recipients with type 1 diabetes who received only a kidney. The best kidney allograft survival was for patients who received a living donor kidney followed by PAK. Receiving a living donor kidney was associated with increased pancreas allograft survival compared with receiving a deceased donor kidney. PAK transplant recipients who receive both organs have a survival advantage compared with uremic candidates who receive neither (SPK waitlist). Compared with uremic diabetic waitlist patients, SPK and PAK recipients showed similar overall patient survival. Successful PAK offers a survival advantage compared with receiving neither a kidney nor a pancreas transplant. These data also suggest that receiving a pancreas (after kidney) transplant may have a protective effect on the kidney allograft.