Toll-like receptors TLR2 and TLR4 block the replication of pancreatic ß cells in diet-induced obesity.

Consumption of a high-energy Western diet triggers mild adaptive ß cell proliferation to compensate for peripheral insulin resistance; however, the underlying molecular mechanism remains unclear. In the present study we show that the toll-like receptors TLR2 and TLR4 inhibited the diet-induced replication of ß cells in mice and humans. The combined, but not the individual, loss of TLR2 and TLR4 increased the replication of ß cells, but not that of α cells, leading to enlarged ß cell area and hyperinsulinemia in diet-induced obesity. Loss of TLR2 and TLR4 increased the nuclear abundance of the cell cycle regulators cyclin D2 and Cdk4 in a manner dependent on the signaling mediator Erk. These data reveal a regulatory mechanism controlling the proliferation of ß cells in diet-induced obesity and suggest that selective targeting of the TLR2/TLR4 pathways may reverse ß cell failure in patients with diabetes.

Postmodification with Polycations Enhances Key Properties of Alginate-Based Multicomponent Microcapsules.

Postmodification of alginate-based microspheres with polyelectrolytes (PEs) is commonly used in the cell encapsulation field to control microsphere stability and permeability. However, little is known about how different applied PEs shape the microsphere morphology and properties, particularly in vivo. Here, we addressed this question using model multicomponent alginate-based microcapsules postmodified with PEs of different charge and structure. We found that the postmodification can enhance or impair the mechanical resistance and biocompatibility of microcapsules implanted into a mouse model, with polycations surprisingly providing the best results. Confocal Raman microscopy and confocal laser scanning microscopy (CLSM) analyses revealed stable interpolyelectrolyte complex layers within the parent microcapsule, hindering the access of higher molar weight PEs into the microcapsule core. All microcapsules showed negative surface zeta potential, indicating that the postmodification PEs get hidden within the microcapsule membrane, which agrees with CLSM data. Human whole blood assay revealed complex behavior of microcapsules regarding their inflammatory and coagulation potential. Importantly, most of the postmodification PEs, including polycations, were found to be benign toward the encapsulated model cells.

Simultaneous split liver/kidney transplantation: A national and single center experience report.

BACKGROUND: End-stage liver disease (ESLD) and end-stage renal disease (ESRD) are prevalent diseases for which the definitive treatment is transplantation. With limited organ supply, strategies to maximize organ availability has led to increasing rates of split liver transplantations for ESLD patients. Therefore, simultaneous split liver and kidney transplantations (SSLK) for patients with ESLD and ESRD could represent a treatment option for comorbid patients. However, current practice and outcomes after SSLK are unknown. METHODS: We aim to report national trends and our experience with patients undergoing SSLK. We performed a retrospective review of the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research file from January 2011-April 2022. Descriptive analysis of preoperative characteristics, postoperative outcomes and actuarial graft and patient survivals are reported. RESULTS: National review of the UNOS transplant registry from 2011-2021 of adult patients undergoing initial transplantation via SSLK demonstrates that this procedure remains uncommon, with only 76 such cases captured in that time. Nevertheless, survival rates at 1, 3, and 5 years remains robust, at 94%, 92%, and 90% for patients overall, 90%, 88%, 88%, for the liver graft, and 93%, 91%, 88% for the kidney graft, respectively. Review of a single center experience with three such patients from 2019-2021 has shown a safe, enduring transplant option with no graft complications seen. CONCLUSIONS: SSLK is both safe and a feasible option to optimize organ supply while allowing recipients to receive quality liver and kidney grafts and should be considered more often by transplant centers going forward.

Characterizing the risk of human leukocyte antigen-incompatible living donor kidney transplantation in older recipients.

Older compatible living donor kidney transplant (CLDKT) recipients have higher mortality and death-censored graft failure (DCGF) compared to younger recipients. These risks may be amplified in older incompatible living donor kidney transplant (ILDKT) recipients who undergo desensitization and intense immunosuppression. In a 25-center cohort of ILDKT recipients transplanted between September 24, 1997, and December 15, 2016, we compared mortality, DCGF, delayed graft function (DGF), acute rejection (AR), and length of stay (LOS) between 234 older (age ≥60 years) and 1172 younger (age 18-59 years) recipients. To investigate whether the impact of age was different for ILDKT recipients compared to 17 542 CLDKT recipients, we used an interaction term to determine whether the relationship between posttransplant outcomes and transplant type (ILDKT vs CLDKT) was modified by age. Overall, older recipients had higher mortality (hazard ratio: 1.632.072.65, P < .001), lower DCGF (hazard ratio: 0.360.530.77, P = .001), and AR (odds ratio: 0.390.540.74, P < .001), and similar DGF (odds ratio: 0.461.032.33, P = .9) and LOS (incidence rate ratio: 0.880.981.10, P = 0.8) compared to younger recipients. The impact of age on mortality (interaction P = .052), DCGF (interaction P = .7), AR interaction P = .2), DGF (interaction P = .9), and LOS (interaction P = .5) were similar in ILDKT and CLDKT recipients. Age alone should not preclude eligibility for ILDKT.

Survival after LDLT in recipients ≥70 years old in the United States. An OPTN/UNOS liver transplant registry analysis.

BACKGROUND: Living donor liver transplantation (LDLT) in the elderly population is currently not well studied. There are single-center studies indicating that patient age should not be a barrier to LDLT, with similar outcomes compared to younger recipients. METHODS: Using UNOS/STAR data from 2010 to 2022 we retrospectively analyzed patients ≥70 years old receiving a living donor graft (LDLT ≥70y group) versus a deceased donor graft (DDLT ≥70y group). In addition, we compared recipients ≥70 years old undergoing LDLT versus patients 18-69 years old also undergoing LDLT. Donor and recipient baseline characteristics, as well as postoperative outcomes including graft and patient survival were analyzed and compared between groups. RESULTS: Recipients in the LDLT ≥70y group showed less disease burden and spent significantly less time on the waitlist when compared to recipients in the DDLT ≥70y group (102 [49-201] days versus 170 [36-336] days) respectively; p = .004. With the exception of a longer length of stay (LOS) in the LDLT ≥70y group (p ≤ .001), postoperative outcomes were comparable with recipients in the DDLT ≥70y group, including similar graft and patient survival rates at 1-, 3-, and 5-years. When compared to younger recipients of a graft from a living donor, patients in the LDLT ≥70y group had similar post-transplant functional status, re-transplant rates and similar causes contributing to graft failure. However, significantly lower graft and patient survival rates were observed. CONCLUSION: LDLT for recipients aged 70 or greater represents a faster access to transplantation in a safe and feasible manner when compared to similar- aged recipients undergoing DDLT.

Robotic Assisted Living Donor Nephrectomies: A Safe Alternative to Laparoscopic Technique for Kidney Transplant Donation.

OBJECTIVE: To review outcomes after laparoscopic, robotic-assisted living donor nephrectomy (RLDN) in the first, and largest series reported to date. SUMMARY OF BACKGROUND DATA: Introduction of minimal invasive, laparoscopic donor nephrectomy has increased live kidney donation, paving the way for further innovation to expand the donor pool with RLDN. METHODS: Retrospective chart review of 1084 consecutive RLDNs performed between 2000 and 2017. Patient demographics, surgical data, and complications were collected. RESULTS: Six patients underwent conversion to open procedures between 2002 and 2005, whereas the remainder were successfully completed robotically. Median donor age was 35.7 (17.4) years, with a median BMI of 28.6 (7.7) kg/m2. Nephrectomies were preferentially performed on the left side (95.2%). Multiple renal arteries were present in 24.1%. Median operative time was 159 (54) minutes, warm ischemia time 180 (90) seconds, estimated blood loss 50 (32) mL, and length of stay 3 (1) days. The median follow-up was 15 (28) months. Complications were reported in 216 patients (19.9%), of which 176 patients (81.5%) were minor (Clavien-Dindo class I and II). Duration of surgery, warm ischemia time, operative blood loss, conversion, and complication rates were not associated with increase in body mass index. CONCLUSION: RLDN is a safe technique and offers a reasonable alternative to conventional laparoscopic surgery, in particular in donors with higher body mass index and multiple arteries. It offers transplant surgeons a platform to develop skills in robotic-assisted surgery needed in the more advanced setting of minimal invasive recipient operations.

Split liver transplantation with extended right grafts on adult recipients: A propensity score matching analysis.

INTRODUCTION: Split liver transplantation (SLT) emerged due to its potential to contribute to the organ pool and reduce organ shortage. However, SLT is technically challenging and has been associated with higher rates of postoperative complications leading to concerns about graft and patient survival. Moreover, there are few studies on matched-pair adult recipients of SLT and whole-liver transplant (WLT), with conflicting results. METHODS: This retrospective study analyze outcomes among adults who underwent SLT at our institution from 2010 to 2019. A 1:1 propensity score matching analysis was performed based on important donor and recipient variables. Baseline characteristics and postoperative outcomes were analyzed and compared between groups. Actuarial graft and patient survival were analyzed by KM curves. RESULTS: Out of 592 adults receiving a LT in our institution, 21 SLT adult recipients were identified and matched with 21 adults undergoing WLT. As expected donor age was significantly lower in SLT recipients (16 (15-22) vs. 32 (17-47), P = .012). Additional donor characteristics, including anthropometrics, and ischemic times were similar between groups. Baseline recipient characteristics and postoperative outcomes, including length of stay, vascular complications, biliary complications, and re-transplantation were comparable between SLT and WLT recipients. Graft (95/95/95 vs. 100/94/94, P = .98) and patient (100/100/100 vs. 100/94/94, P = .30) survival at 1-, 3-, 5-years, were similar between the SLT- and WLT group, respectively. CONCLUSION: Split liver transplantation has the potential to increase the availability of organs for adult recipients without compromising individual outcomes.

Living Donor Liver Transplantation vs. Split Liver Transplantation Using Left Lateral Segment Grafts in Pediatric Recipients: An Analysis of the UNOS Database.

Split and LDLT in pediatric patients have the potential to decrease wait times and waitlist mortality. Using UNOS-STAR data, we compared outcomes of pediatric patients undergoing LDLT and SLT using LLS grafts. The baseline characteristics and post-operative outcomes were compared between groups. Actuarial graft and patient survival were analyzed with Kaplan-Meier curves. Between 2010 and 2019, 911 pediatric LT were included in the analysis (LD graft group, n = 508, split graft group, n = 403). LD graft recipients spent more time on the waitlist vs. the split graft group (60 (22-138) days vs. 46 (16-108) days; p = 0.007). LD recipients had a lower rate of graft failure, found in 9.8% of patients compared with 14.6% in the split graft group (p = 0.02). HAT was the most common graft failure cause, with similar rates. Graft and patient survival at 1-, 3-, and 5-years was comparable between LDLT and SLT. In subgroup analyses, patients with biliary atresia, those ≤10 kg or ≤10 years old receiving an LD graft showed improved graft survival. In conclusion, LDLT is associated with a lower rate of graft failure in pediatric patients. The use of LLS regardless of the type of donor is a safe way to facilitate access to transplantation to pediatric patients with acceptable short and long-term outcomes.

Increased use of split liver grafts in adult recipients following implementation of a pediatric liver transplant program.

BACKGROUND: Split liver transplantation (SLT) is a strategy to address organ shortage, but is a technically more demanding procedure than whole graft liver transplantation (LT). We aimed to determine the outcomes following SLT in adult recipients as well as to highlight the impact that having a pediatric LT program has on SLT implementation. METHODS: All SLTs conducted at a single-center from 2010 to 2019 were identified. Patient data was obtained through retrospective review of the electronic medical record. Kaplan-Meier analysis assessed primary outcomes of 1-,3-, and 5-year graft and patient survival. RESULTS: We identified 37 SLTs performed at our institution from 2010 to 2019. Twenty-four donated livers resulted in 21 extended right lobes and 16 left lateral segments for adults and pediatrics recipients, respectively. Eighty-one percent (30/37) of the SLTs were performed after introduction of the combined pediatric program in 2016. 13/24 donor livers were split with both grafts allocated and used at our institution and 92% occurred after introduction of the pediatric program. Graft survival rates at 1-, 3-, and 5-years were 94% in adult recipients and 100% for all time periods in pediatric recipients. Actuarial post-transplant patient survival was 100% at 1-, 3-, and 5-years in both. CONCLUSIONS: The introduction of a pediatric liver transplantation program resulted in more than a fourfold increase in the number of SLTs performed at our center. Increase in allocation and use of both grafts at our institution was also seen.

Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes.

Allogeneic islet transplant offers a minimally invasive option for ß cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c  ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P < .001 for all vs baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health-related and diabetes-related quality of life. The procedure was safe and kidney allograft function remained stable after 3 years. These results add to evidence establishing allogeneic islet transplant as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post-renal transplant setting.

First World Consensus Conference on pancreas transplantation: Part II - recommendations.

The First World Consensus Conference on Pancreas Transplantation provided 49 jury deliberations regarding the impact of pancreas transplantation on the treatment of diabetic patients, and 110 experts' recommendations for the practice of pancreas transplantation. The main message from this consensus conference is that both simultaneous pancreas-kidney transplantation (SPK) and pancreas transplantation alone can improve long-term patient survival, and all types of pancreas transplantation dramatically improve the quality of life of recipients. Pancreas transplantation may also improve the course of chronic complications of diabetes, depending on their severity. Therefore, the advantages of pancreas transplantation appear to clearly surpass potential disadvantages. Pancreas after kidney transplantation increases the risk of mortality only in the early period after transplantation, but is associated with improved life expectancy thereafter. Additionally, preemptive SPK, when compared to SPK performed in patients undergoing dialysis, appears to be associated with improved outcomes. Time on dialysis has negative prognostic implications in SPK recipients. Increased long-term survival, improvement in the course of diabetic complications, and amelioration of quality of life justify preferential allocation of kidney grafts to SPK recipients. Audience discussions and live voting are available online at the following URL address: http://mediaeventi.unipi.it/category/1st-world-consensus-conference-of-pancreas-transplantation/246.

Delayed graft function and acute rejection following HLA-incompatible living donor kidney transplantation.

Incompatible living donor kidney transplant recipients (ILDKTr) have pre-existing donor-specific antibody (DSA) that, despite desensitization, may persist or reappear with resulting consequences, including delayed graft function (DGF) and acute rejection (AR). To quantify the risk of DGF and AR in ILDKT and downstream effects, we compared 1406 ILDKTr to 17 542 compatible LDKT recipients (CLDKTr) using a 25-center cohort with novel SRTR linkage. We characterized DSA strength as positive Luminex, negative flow crossmatch (PLNF); positive flow, negative cytotoxic crossmatch (PFNC); or positive cytotoxic crossmatch (PCC). DGF occurred in 3.1% of CLDKT, 3.5% of PLNF, 5.7% of PFNC, and 7.6% of PCC recipients, which translated to higher DGF for PCC recipients (aOR = 1.03 1.682.72 ). However, the impact of DGF on mortality and DCGF risk was no higher for ILDKT than CLDKT (p interaction > .1). AR developed in 8.4% of CLDKT, 18.2% of PLNF, 21.3% of PFNC, and 21.7% of PCC recipients, which translated to higher AR (aOR PLNF = 1.45 2.093.02 ; PFNC = 1.67 2.403.46 ; PCC = 1.48 2.243.37 ). Although the impact of AR on mortality was no higher for ILDKT than CLDKT (p interaction = .1), its impact on DCGF risk was less consequential for ILDKT (aHR = 1.34 1.621.95 ) than CLDKT (aHR = 1.96 2.292.67 ) (p interaction = .004). Providers should consider these risks during preoperative counseling, and strategies to mitigate them should be considered.

Donor Morbidity Is Equivalent Between Right and Left Hepatectomy for Living Liver Donation: A Meta-Analysis.

Maximizing liver graft volume benefits the living donor liver recipient. Whether maximizing graft volume negatively impacts living donor recovery and outcomes remains controversial. Patient randomization between right and left hepatectomy has not been possible due to anatomic constraints; however, a number of published, nonrandomized observational studies summarize donor outcomes between 2 anatomic living donor hepatectomies. This meta-analysis compares donor-specific outcomes after right versus left living donor hepatectomy. Systematic searches were performed via PubMed, Cochrane, ResearchGate, and Google Scholar databases to identify relevant studies between January 2005 and November 2019. The primary outcomes compared overall morbidity and incidence of severe complications (Clavien-Dindo >III) between right and left hepatectomy in donors after liver donation. Random effects meta-analysis was performed to derive summary risk estimates of outcomes. A total of 33 studies (3 prospective and 30 retrospective cohort) were used to identify 7649 pooled patients (5993 right hepatectomy and 1027 left hepatectomy). Proportion of donors who developed postoperative complications did not significantly differ after right hepatectomy (0.33; 95% confidence interval [CI], 0.27-0.40) and left hepatectomy (0.23; 95% CI, 0.17-0.29; P = 0.19). The overall risk ratio (RR) did not differ between right and left hepatectomy (RR, 1.16; 95% CI, 0.83-1.63; P = 0.36). The relative risk for a donor to develop severe complications showed no differences by hepatectomy side (Incidence rate ratio, 0.97; 95% CI, 0.67-1.40; P = 0.86). There is no evidence that the overall morbidity differs between right and left lobe donors. Publication bias reflects institutional and surgeon variation. A prospective, standardized, multi-institutional study would help quantify the burden of donor complications after liver donation.

Robotic kidney transplantation in the obese patient: 10-year experience from a single center.

Despite increasing obesity rates in the dialysis population, obese kidney transplant candidates are still denied transplantation by many centers. We performed a single-center retrospective analysis of a robotic-assisted kidney transplant (RAKT) cohort from January 2009 to December 2018. A total of 239 patients were included in this analysis. The median BMI was 41.4 kg/m2 , with the majority (53.1%) of patients being African American and 69.4% of organs sourced from living donors. The median surgery duration and warm ischemia times were 4.8 hours and 45 minutes respectively. Wound complications (mostly seromas and hematomas) occurred in 3.8% of patients, with 1 patient developing a surgical site infection (SSI). Seventeen (7.1%) graft failures, mostly due to acute rejection, were reported during follow-up. Patient survival was 98% and 95%, whereas graft survival was 98% and 93%, at 1 and 3 years respectively. Similar survival statistics were obtained from patients undergoing open transplant over the same time period from the UNOS database. In conclusion, RAKT can be safely performed in obese patients with minimal SSI risk, excellent graft function, and patient outcomes comparable to national data. RAKT could improve access to kidney transplantation in obese patients due to the low surgical complication rate.

Long-term implant fibrosis prevention in rodents and non-human primates using crystallized drug formulations.

Implantable medical devices have revolutionized modern medicine. However, immune-mediated foreign body response (FBR) to the materials of these devices can limit their function or even induce failure. Here we describe long-term controlled-release formulations for local anti-inflammatory release through the development of compact, solvent-free crystals. The compact lattice structure of these crystals allows for very slow, surface dissolution and high drug density. These formulations suppress FBR in both rodents and non-human primates for at least 1.3 years and 6 months, respectively. Formulations inhibited fibrosis across multiple implant sites-subcutaneous, intraperitoneal and intramuscular. In particular, incorporation of GW2580, a colony stimulating factor 1 receptor inhibitor, into a range of devices, including human islet microencapsulation systems, electrode-based continuous glucose-sensing monitors and muscle-stimulating devices, inhibits fibrosis, thereby allowing for extended function. We believe that local, long-term controlled release with the crystal formulations described here enhances and extends function in a range of medical devices and provides a generalized solution to the local immune response to implanted biomaterials.

Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors.

BACKGROUND: A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS: In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS: Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS: This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Genetically Encoded, Photostable Indicators to Image Dynamic Zn2+ Secretion of Pancreatic Islets.

As an essential element for living organisms, zinc (Zn2+) exerts its biological functions both intracellularly and extracellularly. Previous studies have reported a number of genetically encoded Zn2+ indicators (GEZIs), which have been widely used to monitor Zn2+ in the cytosol and intracellular organelles. However, it is challenging to localize existing GEZIs to the extracellular space to detect secreted Zn2+. Herein, we report two photostable, green fluorescent protein (GFP) based indicators, ZIBG1 and ZIBG2, which respond to Zn2+ selectively and have affinities suited for detecting Zn2+ secretion from intracellular vesicles. In particular, ZIBG2 can be effectively targeted to the extracellular side of plasma membrane. We applied cell surface-localized ZIBG2 to monitor glucose-induced dynamic Zn2+ secretion from mouse insulinoma MIN6 cells and primary mouse and human pancreatic islets. Because Zn2+ is co-released with insulin from ß-cells, the fluorescence of cell surface-localized ZIBG2 was shown to be a strong indicator for the functional potency of islets. Our work here has thus expanded the use of GEZIs to image dynamic Zn2+ secretion in live tissue. Because it is convenient to use genetically encoded indicators for expression over extended periods and for in vivo delivery, we envision future applications of ZIBG2 in development of induced ß-cells or islets to advance cell replacement therapies for diabetes and in direct imaging of Zn2+ secretion dynamics in vivo.

Hospital readmissions following HLA-incompatible live donor kidney transplantation: A multi-center study.

Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care.

Colony stimulating factor-1 receptor is a central component of the foreign body response to biomaterial implants in rodents and non-human primates.

Host recognition and immune-mediated foreign body response to biomaterials can compromise the performance of implanted medical devices. To identify key cell and cytokine targets, here we perform in-depth systems analysis of innate and adaptive immune system responses to implanted biomaterials in rodents and non-human primates. While macrophages are indispensable to the fibrotic cascade, surprisingly neutrophils and complement are not. Macrophages, via CXCL13, lead to downstream B cell recruitment, which further potentiated fibrosis, as confirmed by B cell knockout and CXCL13 neutralization. Interestingly, colony stimulating factor-1 receptor (CSF1R) is significantly increased following implantation of multiple biomaterial classes: ceramic, polymer and hydrogel. Its inhibition, like macrophage depletion, leads to complete loss of fibrosis, but spares other macrophage functions such as wound healing, reactive oxygen species production and phagocytosis. Our results indicate that targeting CSF1R may allow for a more selective method of fibrosis inhibition, and improve biomaterial biocompatibility without the need for broad immunosuppression.

Long term (4 years) improved insulin sensitivity following islet cell transplant in type 1 diabetes.

BACKGROUND: Impaired insulin sensitivity (IS) predicts complications and mortality in type 1 diabetes (T1D). Insulin sensitivity improves shortly after islet cell transplant for T1D, yet long-term changes in IS and associated factors such as patient characteristics, transplant factors, clinical management, and IS-related biomarkers are unknown. METHODS: Up to 9 years (mean 4) of longitudinal data were available on 22 adults (18 female) with T1D who received 1 to 3 transplants in Phase 1/2 or 3 clinical trials (2004-2014). Metabolic testing posttransplant estimated IS by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR; 111 observations) and the Simple Index of Insulin Sensitivity (SIis ; 95 observations). RESULTS: Simple Index of Insulin Sensitivity significantly increased the first year posttransplant (P = .02), then stabilized (P = .39); HOMA-IR remained stable posttransplant (P = .92). Adjusting for age and BMI, higher SIis was associated with lower HbA1c following transplant (P = .03). Greater IS as measured by lower HOMA-IR and higher SIis was associated with lower fasting C-peptide (both P ≤ .04) and also with higher exenatide dose (both P ≤ .01). More islets transplanted were associated with higher SIis (P < .0001). Lower leptin at transplant predicted lower HOMA-IR and higher SIis after transplant, and lower bone marker receptor activator of nuclear factor kappa-B ligand predicted lower HOMA-IR (all P ≤ .01). CONCLUSIONS: Insulin sensitivity measured by SIis was improved several years following transplant, while IS measured by HOMA-IR did not worsen. Higher exenatide dose, more islets transplanted, and diet and exercise (lowering leptin and receptor activator of nuclear factor kappa-B ligand) may improve IS, which may enhance glycaemic control and lower metabolic demand on transplanted islets. Long-term clamp studies are needed to confirm these results.