Targeting CXCR1/2 in the first multicenter, double-blinded, randomized trial in autologous islet transplant recipients.

Several cytokines and chemokines are elevated after islet infusion in patients undergoing total pancreatectomy with islet autotransplantation (TPIAT), including CXCL8 (also known as interleukin-8), leading to islet loss. We investigated whether use of reparixin for blockade of the CXCL8 pathway would improve islet engraftment and insulin independence after TPIAT. Adults without diabetes scheduled for TPIAT at nine academic centers were randomized to a continuous infusion of reparixin or placebo (double-blinded) for 7 days in the peri-transplant period. Efficacy measures included insulin independence (primary), insulin dose, hemoglobin A1c (HbA1c ), and mixed meal tolerance testing. The intent-to-treat population included 102 participants (age 39.5 ± 12.2 years, 69% female), n = 50 reparixin-treated, n = 52 placebo-treated. The proportion insulin-independent at Day 365 was similar in reparixin and placebo: 20% vs. 21% (p = .542). Twenty-seven of 42 (64.3%) in the reparixin group and 28/45 (62.2%) in the placebo group maintained HbA1c ≤6.5% (p = .842, Day 365). Area under the curve C-peptide from mixed meal testing was similar between groups, as were adverse events. In conclusion, reparixin infusion did not improve diabetes outcomes. CXCL8 inhibition alone may be insufficient to prevent islet damage from innate inflammation in islet autotransplantation. This first multicenter clinical trial in TPIAT highlights the potential for future multicenter collaborations.

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.

COVID-19 in hospitalized liver transplant recipients: An early systematic review and meta-analysis.

Adverse clinical outcomes related to SARS-CoV-2 infection among liver transplant (LTx) recipients remain undefined. We performed a meta-analysis to determine the pooled prevalence of outcomes among hospitalized LTx recipients with COVID-19. A database search of literature published between December 1, 2019, and November 20, 2020, was performed per PRISMA guidelines. Twelve studies comprising 517 hospitalized LTx recipients with COVID-19 were analyzed. Common presenting symptoms were fever (71%), cough (62%), dyspnea (48%), and diarrhea (28%). Approximately 77% (95% CI, 61%-93%) of LTx recipients had a history of liver cirrhosis. The most prevalent comorbidities were hypertension (55%), diabetes (45%), and cardiac disease (21%). In-hospital mortality was 20% (95% CI, 13%-28%) and rose to 41% (95% CI, 19%-63%) (P < 0.00) with ICU admission. Additional subgroup analysis demonstrated a higher mortality risk in the elderly (>60-65 years) (OR 4.26; 95% CI, 2.14-8.49). There was no correlation in respect to sex or time since transplant. In summary, LTx recipients with COVID-19 had a high prevalence of dyspnea and gastrointestinal symptoms. In-hospital mortality was comparable to non-transplant populations with similar comorbidities but appeared to be less than what is reported elsewhere for cirrhotic patients (26%-40%). Importantly, the observed high case fatality in the elderly could be due to age-associated comorbidities.

Pain resolution and glucose control in pediatric patients with chronic pancreatitis after total pancreatectomy with islet auto-transplantation.

BACKGROUND: Chronic pancreatitis (CP) and acute recurrent pancreatitis (ARP) in pediatric patients are strongly associated with genetic mutations and lead to pan-parenchymal disease refractory to medical and endoscopic treatment. Our aim was to assess pain resolution and glucose control in patients with CP and ARP following total pancreatectomy with islet auto-transplantation (TPIAT). METHODS: We retrospectively analyzed prospectively collected clinical data of 12 children who developed CP and ARP and underwent TPIAT when 21 years old or younger at the University of Chicago between December 2009 and June 2020. Patients with recurrent or persistent abdominal pain attributed to acute or chronic pancreatic inflammation and a history of medical interventions attempted for the relief of pancreatic pain were selected by a multi-disciplinary team for TPIAT. We followed patients post-operatively and reported data for pre-TPIAT, post-operative day 75, and yearly post-TPIAT. RESULTS: All 12 patients experienced complete resolution of pancreatic pain. The overall insulin-independence rate after 1 year was 66% (8/12) and 50% (3/6) at 4 years. Shorter duration of CP/ARP pre-TPIAT, higher mass of islets infused, and lower BMI, BMI percentile, and BSA were associated with insulin-independence post-TPIAT. CONCLUSIONS: TPIAT is a viable treatment option for pediatric patients with CP and ARP. Pediatric patients undergoing TPIAT for CP achieved resolution of pancreatic-type pain and reduced opioid requirements. The majority were able to achieve insulin-independence which was associated with lower pre-TPIAT BMI and higher islet mass transplanted (i.e., over 2000 IEQ/kg), the latter of which can be achieved by earlier TPIAT. LEVEL OF EVIDENCE: Treatment study, Level IV.

BETA-2 score is an early predictor of graft decline and loss of insulin independence after pancreatic islet allotransplantation.

This study aimed to evaluate whether the BETA-2 score is a reliable early predictor of graft decline and loss of insulin independence after islet allotransplantation. Islet transplant procedures were stratified into 3 groups according to clinical outcome: long-term insulin independence without islet graft decline (group 1, N = 9), initial insulin independence with subsequent islet graft decline and loss of insulin independence (group 2, N = 13), and no insulin independence (group 3, N = 13). BETA-2 was calculated on day 75 and multiple times afterwards for up to 145 months posttransplantation. A BETA-2 score cut-off of 17.4 on day 75 posttransplantation was discerned between group 1 and groups 2 and 3 (area under the receiver operating characteristic 0.769, P = .005) with a sensitivity and negative predictive value of 100%. Additionally, BETA-2 ≥ 17.4 at any timepoint during follow-up reflected islet function required for long-term insulin independence. While BETA-2 did not decline below 17.4 for each of the 9 cases from group 1, the score decreased below 17.4 for all transplants from group 2 with subsequent loss of insulin independence. The reduction of BETA-2 below 17.4 predicted 9 (1.5-21) months in advance subsequent islet graft decline and loss of insulin independence (P = .03). This finding has important implications for posttransplant monitoring and patient care.

Assessment of simple indices based on a single fasting blood sample as a tool to estimate beta-cell function after total pancreatectomy with islet autotransplantation - a prospective study.

We investigated six indices based on a single fasting blood sample for evaluation of the beta-cell function after total pancreatectomy with islet autotransplantation (TP-IAT). The Secretory Unit of Islet Transplant Objects (SUITO), transplant estimated function (TEF), homeostasis model assessment (HOMA-2B%), C-peptide/glucose ratio (CP/G), C-peptide/glucose creatinine ratio (CP/GCr) and BETA-2 score were compared against a 90-min serum glucose level, weighted mean C-peptide in mixed meal tolerance test (MMTT), beta score and the Igls score adjusted for islet function in the setting of IAT. We analyzed values from 32 MMTTs in 15 patients after TP-IAT with a follow-up of up to 3 years. Four (27%) individuals had discontinued insulin completely prior to day 75, while 6 out of 12 patients (50%) did not require insulin support at 1-year follow-up with HbA1c 6.0% (5.5-6.8). BETA-2 was the most consistent among indices strongly correlating with all reference measures of beta-cell function (r = 0.62-0.68). In addition, it identified insulin independence (cut-off = 16.2) and optimal/good versus marginal islet function in the Igls score well, with AUROC of 0.85 and 0.96, respectively. Based on a single fasting blood sample, BETA-2 score has the most reliable discriminant value for the assessment of graft function in patients undergoing TP-IAT.

Comparative evaluation of simple indices using a single fasting blood sample to estimate beta cell function after islet transplantation.

Six single fasting blood sample-based indices-Secretory Unit of Islet Transplant Objects (SUITO), Transplant Estimated Function (TEF), Homeostasis Model Assessment (HOMA)2-B%, C-peptide/glucose ratio (CP/G), C-peptide/glucose creatinine ratio (CP/GCr), and BETA-2 score-were compared against commonly used 90-minute mixed meal tolerance test (MMTT) serum glucose and beta score to assess which of them best recognizes the state of acceptable blood glucose control without insulin supplementation after islet allotransplantation (ITx). We also tested whether the indices could identify the success of ITx based on the Igls classification of beta cell graft function. We analyzed values from 47 MMTT tests in 4 patients with up to 140 months follow-up and from 54 MMTT tests in 13 patients with up to 42 months follow-up. SUITO, CP/G, HOMA2-B%, and BETA-2 correlated well with the 90-minute glucose of the MMTT and beta-score (r 0.54-0.76), whereas CP/GCr showed a modest performance (r 0.41-0.52) while TEF showed little correlation. BETA-2 and SUITO were the best identifiers and predictors of the need for insulin support, glucose intolerance, and ITx success (P < .001), while HOMA2-B% and TEF were unreliable. Single fasting blood sample SUITO and BETA-2 scores are very practical alternative tools that allow for frequent assessments of graft function.

Persistence of long-term insulin independence after islet transplantation and two subsequent pregnancies.

Pregnancy increases metabolic demand for insulin and may lead to the exhaustion of intraportally transplanted islets and post-gestational hyperglycemia. To prevent these complications, we implemented preemptive insulin supplementation during two subsequent pregnancies in an insulin-independent islet transplant recipient. This strategy resulted in optimal blood glucose control during the pregnancies, the preservation of the optimal islet graft function and the postpartum maintenance of long-term insulin independence.

The Seattle Heart Failure Model in Kidney Transplant Recipients.

Cardiovascular disease is the leading cause of mortality following kidney transplantation. Heart failure affects 17-21% of patients with chronic kidney disease and increases along with time receiving dialysis. The Seattle Heart Failure Model (SHFM) is a validated mortality risk model for heart failure patients that incorporates clinical, therapeutic, and laboratory parameters but does not include measures of kidney function. We applied the SHFM to patients with end-stage renal disease (ESRD) who were being evaluated for kidney transplantation to determine if the model was associated with post-transplant mortality. This retrospective single-center study analyzed survival among 360 adult deceased-donor kidney transplant recipients. Cox regression was used to model post-transplant patient survival. Our findings indicated that a 1.0-point increase in the adapted SHFM score was significantly associated with post-transplant mortality (HR 1.76, 95% CI = 1.10-2.83, p = 0.02), independently of the Kidney Donor Profile Index and Estimated Post-Transplant Survival. Individual covariates of the SHFM were evaluated in univariate analyses, and age, sodium, cholesterol, and lymphocyte count were significantly related to mortality. This study provides preliminary evidence that an adapted SHFM score could be a useful tool in evaluating mortality risk post-transplant in patients with ESRD.

The impact of full-spectrum endoscopy on pathological lesion detection in different regions of the colon: a randomised, controlled trial.

INTRODUCTION: Colonoscopy is crucial for detecting and localising pathological lesions within the colon. Colonoscopy quality is defined by the caecal intubation rate, withdrawal time, adenoma detection rate, and polyp detection rate. The newly introduced full-spectrum endoscope (FUSE®) provides a 330° field of view, allowing endoscopists to observe more colonic anatomy. It is intended to increase detection of pathological lesions, especially those situated behind the haustral folds of the bowel. This diagnostic modality should increase the adenoma detection rate (ADR), especially in the right hemicolon. The aim of this study was to explore the efficacy of FUSE for detecting pathologic lesions in different colonic regions. MATERIAL AND METHODS: The study enrolled 408 patients who were randomised to either a standard frontal view (SFV) or the novel full-spectrum colonoscopy. Analysis was performed among three broad regions of the colon: right, transverse, and left colon, according to the Boston Bowel Preparation Scale. RESULTS: FUSE yielded a higher diverticula detection rate (DDR) in the right and middle colon (DDR-R (p < 0.05), DDR-T (p < 0.05), DDR-L (p = 0.862)). ADR (p = 0.761), advanced ADR (aADR) (p = 0.950), and DDR (p = 0.967) in respective regions of the colon were similar between the groups; however, the total number of adenomas detected with FUSE was higher in the right and middle regions of the colon compared with those detected by SFV (p < 0.05). CONCLUSIONS: Full-spectrum colonoscopy allows for effective recognition of pathological lesions in the right and middle regions of the colon. Although full-spectrum colonoscopy did not statistically affect ADR, the absolute number of adenomas detected was higher compared with classical endoscopy.

Arterial Intimal Fibrosis in Reperfusion Biopsy Correlates with Graft Function after Kidney Transplant.

INTRODUCTION: Alterations to the procurement biopsy are one of the main reasons that kidneys are not suitable for transplant and are discarded. The literature on procurement and reperfusion biopsy is inconsistent and heterogeneous. The objective of this study is to describe the correlation of the different histological characteristics detected by the procurement and reperfusion biopsies in relation to graft function. METHODS: This is a retrospective cohort study of deceased donor kidney transplants performed from 2013 to 2017. All of the different histological components of procurement and reperfusion biopsies were analyzed with nonparametric tests and multivariate regressions. Graft function was expressed as glomerular filtration rate (GFR) at 1, 3, 6, and 12 months after transplant. All tests were based on a level of significance of α = 0.05. RESULTS: A comparison of procurement and reperfusion biopsies revealed that 60.4% of the grafts exhibited more arterial intimal fibrosis and 55.6% more arteriolar hyalinosis in the reperfusion biopsy than in the procurement biopsy. Arterial intimal fibrosis in reperfusion biopsy correlated with GFR at all time points, and it was the only histological characteristic of the reperfusion biopsy that remained significant in multivariate analysis. Glomerulosclerosis in the procurement biopsy correlated with graft function and remained significant in multivariate analysis, but only at 6 months. Arterial intimal fibrosis in the reperfusion biopsy is significantly associated with graft function independently of clinical characteristics. CONCLUSION: Our study highlights the importance of arterial intimal fibrosis in predicting kidney function after transplant. Because arterial intimal fibrosis is a chronic change not related to ischemia-reperfusion injury, the differences between the 2 biopsies may be due to the biopsy technique. In order to increase the prognostic accuracy of the procurement biopsy, the technique should be improved to better evaluate the vasculature.

Evaluating the Prognostic Value of Islet Autoantibody Monitoring in Islet Transplant Recipients with Long-Standing Type 1 Diabetes Mellitus.

(1) Background: The correlation between titers of islet autoantibodies (IAbs) and the loss of transplanted islets remains controversial. We sought to evaluate the prognostic utility of monitoring IAbs in diabetic patients after islet transplantation (ITx); (2) Methods: Twelve patients with Type 1 diabetes mellitus and severe hypoglycemia underwent ITx. Serum concentration of glutamic acid decarboxylase (GAD), insulinoma antigen 2 (IA-2), and zinc transport 8 (ZnT8) autoantibodies was assessed before ITx and 0, 7, and 75 days and every 3 months post-operatively; (3) Results: IA-2A (IA-2 antibody) and ZnT8A (ZnT8 antibody) levels were not detectable before or after ITx in all patients (median follow-up of 53 months (range 24-61)). Prior to ITx, GAD antibody (GADA) was undetectable in 67% (8/12) of patients. Of those, 75% (6/8) converted to GADA+ after ITx. In 67% (4/6) of patients with GADA+ seroconversion, GADA level peaked within 3 months after ITx and subsequently declined. All patients with GADA+ seroconversion maintained long-term partial or complete islet function (insulin independence) after 1 or 2 ITx. There was no correlation between the presence of IAb-associated HLA haplotypes and the presence of IAbs before or after ITx; (4) Conclusions: There is no association between serum GADA trends and ITx outcomes. IA-2A and ZnT8A were not detectable in any of our patients before or after ITx.

The Impact of COVID-19 on Kidney Transplant Recipients in Pre-Vaccination and Delta Strain Era: A Systematic Review and Meta-Analysis.

Herein, we performed a meta-analysis of published clinical outcomes of corona virus disease 2019 (COVID-19) in hospitalized kidney transplant recipients. A systematic database search was conducted between December 1, 2019 and April 20, 2020. We analyzed 48 studies comprising 3137 kidney transplant recipients with COVID-19. Fever (77%), cough (65%), dyspnea (48%), and gastrointestinal symptoms (28%) were predominant on hospital admission. The most common comorbidities were hypertension (83%), diabetes mellitus (34%), and cardiac disease (23%). The pooled prevalence of acute respiratory distress syndrome and acute kidney injury were 58% and 48%, respectively. Invasive ventilation and dialysis were required in 24% and 22% patients, respectively. In-hospital mortality rate was as high as 21%, and increased to over 50% for patients in intensive care unit (ICU) or requiring invasive ventilation. Risk of mortality in patients with acute respiratory distress syndrome (ARDS), on mechanical ventilation, and ICU admission was increased: OR = 19.59, OR = 3.80, and OR = 13.39, respectively. Mortality risk in the elderly was OR = 3.90; however, no such association was observed in terms of time since transplantation and gender. Fever, cough, dyspnea, and gastrointestinal symptoms were common on admission for COVID-19 in kidney transplant patients. Mortality was as high as 20% and increased to over 50% in patients in ICU and required invasive ventilation.

Islets Transplantation at a Crossroads - Need for Urgent Regulatory Update in the United States: Perspective Presented During the Scientific Sessions 2021 at the American Diabetes Association Congress.

Clinical islet allotransplantation has been successfully regulated as tissue/organ for transplantation in number of countries and is recognized as a safe and efficacious therapy for selected patients with type 1 diabetes mellitus. However, in the United States, the FDA considers pancreatic islets as a biologic drug, and islet transplantation has not yet shifted from the experimental to the clinical arena for last 20 years. In order to transplant islets, the FDA requires a valid Biological License Application (BLA) in place. The BLA process is costly and lengthy. However, despite the application of drug manufacturing technology and regulations, the final islet product sterility and potency cannot be confirmed, even when islets meet all the predetermined release criteria. Therefore, further regulation of islets as drugs is obsolete and will continue to hinder clinical application of islet transplantation in the US. The Organ Procurement and Transplantation Network together with the United Network for Organ Sharing have developed separately from the FDA and BLA regulatory framework for human organs under the Human Resources & Services Administration to assure safety and efficacy of transplantation. Based on similar biologic characteristics of islets and human organs, we propose inclusion of islets into the existing regulatory framework for organs for transplantation, along with continued FDA oversight for islet processing, as it is for other cell/tissue products exempt from BLA. This approach would reassure islet quality, efficacy and access for Americans with diabetes to this effective procedure.

Post-Hoc Analysis of a Randomized, Double Blind, Prospective Study at the University of Chicago: Additional Standardizations of Trial Protocol are Needed to Evaluate the Effect of a CXCR1/2 Inhibitor in Islet Allotransplantation.

A recent randomized, multicenter trial did not show benefit of a CXCR1/2 receptor inhibitor (Reparixin) when analysis included marginal islet mass (>3,000 IEQ/kg) for allotransplantation and when immunosuppression regimens were not standardized among participating centers. We present a post-hoc analysis of trial patients from our center at the University of Chicago who received an islet mass of over 5,000 IEQ/kg and a standardized immunosuppression regimen of anti-thymocyte globulin (ATG) for induction. Twelve islet allotransplantation (ITx) recipients were randomized (2:1) to receive Reparixin (N = 8) or placebo (N = 4) in accordance with the multicenter trial protocol. Pancreas and donor characteristics did not differ between Reparixin and placebo groups. Five (62.5%) patients who received Reparixin, compared to none in the placebo group, achieved insulin independence after only one islet infusion and remained insulin-free for over 2 years (P = 0.08). Following the first ITx with ATG induction, distinct cytokine, chemokine, and miR-375 release profiles were observed for both the Reparixin and placebo groups. After excluding procedures with complications, islet engraftment on post-operative day 75 after a single transplant was higher in the Reparixin group (n = 7) than in the placebo (n = 3) group (P = 0.03) when islet graft function was measured by the ratio of the area under the curve (AUC) for c-peptide to glucose in mixed meal tolerance test (MMTT). Additionally, the rate of engraftment was higher when determined via BETA-2 score instead of MMTT (P = 0.01). Our analysis suggests that Reparixin may have improved outcomes compared to placebo when sufficient islet mass is transplanted and when standardized immunosuppression with ATG is used for induction. However, further studies are warranted. Investigation of Reparixin and other novel agents under more standardized and optimized conditions would help exclude confounding factors and allow for a more definitive evaluation of their role in improving outcomes in islet transplantation. Clinical trial reg. no. NCT01817959, clinicaltrials.gov.

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.

Total pancreatectomy with islet autotransplantation in diabetic and pre-diabetic patients with intractable chronic pancreatitis.

Total pancreatectomy with islet autotransplantation (TPIAT) is an effective treatment option for non-diabetic patients with intractable chronic pancreatitis. The outcome and potential benefits for pre-diabetic and diabetic patients are less well established. Thirty-four patients underwent TPIAT were retrospectively divided into 3 groups according to pre-operative glycemic control: diabetes mellitus (DM) (n=5, 15%), pre-DM (n=11, 32%) and non-DM (n=18, 54%). Pre-operative fasting c-peptide was detectable and similar in all 3 groups. Islet yield in the DM group was comparable to pre-DM and non-DM groups (median islet equivalents [IEQ] was 191,800, 111,800, and 232,000IEQ, respectively). Patients received islet mass of over the target level of 2000IEQ/kg in pre-DM and DM at lower but clinically meaningful rates compared to the non-DM group: 45% (5/11) and 60% (3/5) for a combined 50% (8/16) rate, respectively, compared to 83% (15/18) for the non-DM group. At 1 year, fasting c-peptide and HbA1c did not differ between DM and pre-DM groups but c-peptide was significantly higher in non-DM. Islet transplantation failed (negative c-peptide) only in 1 patient. Pre-operatively, all patients experienced pancreatic pain with daily opioid dependence in 60% to 70%. Pancreatic-type pain gradually subsided completely in all groups with no differences in other painful somatic symptoms. Diabetic patients with measurable pre-operative c-peptide can achieve similar benefit from TPIAT, with comparable outcomes to pre-diabetic and non-diabetic patients including pain relief and the metabolic benefit of transplanted islets. Not surprisingly, endocrine outcomes for diabetic and pre-diabetics patients are substantially worse than in those with normal pre-operative glucose control.