The effect of low titers of donor-specific antibodies (DSAs) detected only by sensitive solid-phase assays (SPAs) on renal transplant outcomes is unclear. We report the results of a systematic review ...and meta-analysis of rejection rates and graft outcomes for renal transplant recipients with such preformed DSAs, defined by positive results on SPA but negative complement-dependent cytotoxicity and flow cytometry crossmatch results. Our search identified seven retrospective cohort studies comprising a total of 1119 patients, including 145 with isolated DSA-SPA. Together, these studies suggest that the presence of DSA-SPA, despite a negative flow cytometry crossmatch result, nearly doubles the risk for antibody-mediated rejection (relative risk RR, 1.98; 95% confidence interval CI, 1.36-2.89; P<0.001) and increases the risk for graft failure by 76% (RR, 1.76; 95% CI, 1.13-2.74; P=0.01). These results suggest that donor selection should consider the presence of antibodies in the recipient, identified by the SPA, even in the presence of a negative flow cytometry crossmatch result.
Generation of surrogate sources of insulin-producing β-cells remains a goal of diabetes therapy. While most efforts have been directed at differentiating embryonic or induced pluripotent stem (iPS) ...cells into β-like-cells through endodermal progenitors, we have shown that gut endocrine progenitor cells of mice can be differentiated into glucose-responsive, insulin-producing cells by ablation of transcription factor Foxo1. Here we show that FOXO1 is present in human gut endocrine progenitor and serotonin-producing cells. Using gut organoids derived from human iPS cells, we show that FOXO1 inhibition using a dominant-negative mutant or lentivirus-encoded small hairpin RNA promotes generation of insulin-positive cells that express all markers of mature pancreatic β-cells, release C-peptide in response to secretagogues and survive in vivo following transplantation into mice. The findings raise the possibility of using gut-targeted FOXO1 inhibition or gut organoids as a source of insulin-producing cells to treat human diabetes.
Geographic disparities in access to deceased donor kidney transplantation persist in the United States under the Kidney Allocation System (KAS) introduced in 2014, and the effect of transplant center ...practices on the probability of transplantation for wait-listed patients remains unclear.
To compare probability of transplantation across centers nationally and within donation service areas (DSAs), we conducted a registry study that included all United States incident adult kidney transplant candidates wait listed in 2011 and 2015 (pre-KAS and post-KAS cohorts comprising 32,745 and 34,728 individuals, respectively). For each center, we calculated the probability of deceased donor kidney transplantation within 3 years of wait listing using competing risk regression, with living donor transplantation, death, and waiting list removal as competing events. We examined associations between center-level and DSA-level characteristics and the adjusted probability of transplant.
Candidates received deceased donor kidney transplants within 3 years of wait listing more frequently post-KAS (22%) than pre-KAS (19%). Nationally, the probability of transplant varied 16-fold between centers, ranging from 4.0% to 64.2% in the post-KAS era. Within DSAs, we observed a median 2.3-fold variation between centers, with up to ten-fold and 57.4 percentage point differences. Probability of transplantation was correlated in the post-KAS cohort with center willingness to accept hard-to-place kidneys (
=0.55,
<0.001) and local organ supply (
=0.44,
<0.001).
Large differences in the adjusted probability of deceased donor kidney transplantation persist under KAS, even between centers working with the same local organ supply. Probability of transplantation is significantly associated with organ offer acceptance patterns at transplant centers, underscoring the need for greater understanding of how centers make decisions about organs offered to wait-listed patients and how they relate to disparities in access to transplantation.
The best insulin delivery is a human pancreas McCune, Kasi; Owen‐Simon, Nina; Dube, Geoffrey K ...
Clinical transplantation,
April 2023, 2023-04-00, 20230401, Letnik:
37, Številka:
4
Journal Article
Recenzirano
Purpose
We wanted to compare glycemic control post pancreas transplantation with newer therapeutic options.
Methods
We conducted a retrospective analysis of pancreas transplantation at our ...institution from January 1, 2008, through September 30, 2021. All patients who underwent pancreatic transplantation were 18 years and older. We compared pre‐transplant glycemic control of those patients, whether self‐monitoring or continuous glucose monitor to their post‐transplant glycemic control. Outcomes were assessed by HgbA1C level at evaluation (eval), pretransplant (pre), within the first 5 months posttransplant (post) and 1 year post transplant (1 year).
Results
One hundred and thirty‐four patients underwent pancreas transplantation during the 14‐year study period. Overall, 1‐year patient and graft survival were 95% and 88%. The mean HgbA1C (%) for eval and pre were 8.5(SD ± 1.7) and 8.3(SD ± 1.7), which was significantly higher than post, and 1 year at 5.1(SD ± .6, p < .01) and 5.2(SD ± .6, p < .01). Of those, 38 patients presented with continuous glucose monitors (CGM) +/− pump. Their mean HgbA1C(%) was 8.2(SD ± 1.5) at eval 8.1(SD ± 1.3). These were also significantly higher than post 5.0(SD ± .6, p < .01), and 1 year 5.1(SD ± .5, p < .01).
Conclusion
Pancreas transplant provides superior glycemic control to continuous glucose monitoring and remains the optimal therapy for appropriately selected patients with diabetes.
As a highly regenerative organ, the intestine is a promising source for cellular reprogramming for replacing lost pancreatic β cells in diabetes. Gut enterochromaffin cells can be converted to ...insulin-producing cells by forkhead box O1 (FoxO1) ablation, but their numbers are limited. In this study, we report that insulin-immunoreactive cells with Paneth/goblet cell features are present in human fetal intestine. Accordingly, lineage-tracing experiments show that, upon genetic or pharmacologic FoxO1 ablation, the Paneth/goblet lineage can also undergo conversion to the insulin lineage. We designed a screening platform in gut organoids to accurately quantitate β-like cell reprogramming and fine-tune a combination treatment to increase the efficiency of the conversion process in mice and human adult intestinal organoids. We identified a triple blockade of FOXO1, Notch, and TGF-β that, when tested in insulin-deficient streptozotocin (STZ) or NOD diabetic animals, resulted in near normalization of glucose levels, associated with the generation of intestinal insulin-producing cells. The findings illustrate a therapeutic approach for replacing insulin treatment in diabetes.
Biopsy findings at the time of procurement of deceased donor kidneys remain the most common reason cited for kidney discard. To determine the value of renal allograft histology in predicting ...outcomes, we evaluated the significance of histologic findings, read by experienced renal pathologists, in 975 postreperfusion biopsy specimens collected from 2005 to 2009 after living donor (
=427) or deceased donor (
=548) renal transplant. We evaluated specimens for the degree of glomerulosclerosis, interstitial fibrosis and tubular atrophy, and vascular disease; specimens with a score of 0 or 1 (scale, 0-3) for each parameter were considered optimal. Overall, 66.3% of living donor kidneys and 50.7% of deceased donor kidneys received an optimal histology score (
<0.001). Irrespective of donor status, suboptimal kidneys came from older donors with a higher incidence of diabetes mellitus, hypertension, and obesity and a higher mean kidney donor risk index (all
<0.001). Death-censored outcomes after transplant differed significantly between optimal and suboptimal kidneys only in the deceased donor transplants (
=0.02). Regardless of histologic classification, outcomes with deceased donor kidneys were inferior to outcomes with living donor kidneys. However, 73.2% of deceased donor kidneys with suboptimal histology remained functional at 5 years. Our findings suggest that histologic findings on postreperfusion biopsy associate with outcomes after deceased donor but not living donor renal transplants, thus donor death and organ preservation-related factors may be of greater prognostic importance. Discarding donated kidneys on the basis of histologic factors may be inappropriate and merits further study.
There are limited data on the nonprocurement of kidneys from solid organ donors. Analysis of Standard Transplant Analysis and Research files was undertaken on all deceased donors in the United States ...with at least 1 solid organ recovered. From 2000 to 2018, 21 731 deceased donor kidneys (averaging 1144 kidneys per year) were not procured. No kidneys were procured from 8% of liver donors, 3% of heart donors, and 3% of lung donors. Compared to donors with all kidneys procured, those with none procured were older and more likely obese, black, hypertensive, diabetic, hepatitis C positive, smokers, Public Health Service – Increased Risk designated, deceased after cardiac death, or deceased after cerebrovascular accident. Although these donors had lower quality kidneys (median Kidney Donor Risk Index (interquartile range) 1.9 (1.0) vs 1.2 (0.7)), there was substantial overlap in quality between nonprocured and procured kidneys. Nearly one third of nonprocurements were attributed to donor history. Donors with elevated terminal creatinine likely resulting from acute kidney injury (AKI) had higher odds of kidney nonprocurement. Nonprocurement odds varied widely across Organ Procurement and Transplantation Network regions, with a positive correlation between donor kidney nonprocurements and kidney discards at the donation service area level. These findings suggest current discard rates underestimate the underutilization of deceased donor kidneys and more research is needed to optimize safe procurement and utilization of kidneys from donors with AKI.
In this analysis of deceased donors in the United States between 2000–2018, the authors show that kidney nonprocurement, despite procurement of a lung, heart, or liver, was associated with donor history and elevated terminal creatinine that likely reflect donor acute kidney injury.
An increasing number of patients on the waitlist for a kidney transplant indicates a need to effectively utilize as many deceased donor kidneys as possible while ensuring acceptable outcomes. ...Assessing regional and center-level organ utilization with regards to discard can reveal regional variation in suboptimal deceased donor kidney acceptance patterns stemming from perceptions of risk.
We created a weighted donor utilization index from a logistic regression model using high-risk donor characteristics and discard rates from 113,640 deceased donor kidneys procured for transplant from 2010 to 2016, and used it to examine deceased donor kidney utilization in 182 adult transplant centers with >15 annual deceased donor kidney transplants. Linear regression and correlation were used to analyze differences in donor utilization indexes.
The donor utilization index was found to significantly vary by Organ Procurement and Transplantation Network region (
<0.001), revealing geographic trends in kidney utilization. When investigating reasons for this disparity, there was no significant correlation between center volume and donor utilization index, but the percentage of deceased donor kidneys imported from other regions was significantly associated with donor utilization for all centers (rho=0.39;
<0.001). This correlation was found to be particularly strong for region 4 (rho=0.83;
=0.001) and region 9 (rho=0.82;
=0.001). Additionally, 25th percentile time to transplant was weakly associated with the donor utilization index (
=0.15;
=0.03).
There is marked center-level variation in the use of deceased donor kidneys with less desirable characteristics both within and between regions. Broader utilization was significantly associated with shorter time to transplantation.
In accordance with the National Organ Transplant Act and Department of Health and Human Services’ Final Rule, the Scientific Registry of Transplant Recipients (SRTR) publicly releases biannual ...program‐specific reports that include analyses of transplant centers’ risk‐adjusted waitlist mortality, organ acceptance ratios, transplant rates, and graft and patient survival. Since the inception of these center metrics, 1‐year posttransplant graft and patient survival have improved, and center variation has decreased, casting uncertainty on their clinical relevance. The SRTR has recently modified center evaluations by ranking centers into 5 tiers rather than 3 tiers in an attempt to discriminate between programs performing within a tight range, further exacerbating this uncertainty. The American Society of Transplantation/American Society of Transplant Surgeons convened an expert taskforce to examine both the utility and unintended consequences of transplant center metrics. Estimates of center variation in outcomes in adjacent tiers are imprecise and fleeting, but can result in consequential changes in clinician and center behavior. The taskforce has concerns that current metrics, based principally on 1‐year graft and patient survival, provide minimal if any benefit in informing patient choice and access to transplantation, with the untoward effect of decreased utilization of organs and restriction of research and innovation.
The AST/ASTS Transplant Metrics Taskforce examines the relevance of current program‐specific reporting for kidney transplantation in the modern era.
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