Genetically Modified Porcine Kidneys Have Sufficient Tissue Integrity for Use in Pig-to-Human Xenotransplantation.

OBJECTIVE: We sought to determine if genetically modified porcine kidneys used for xenotransplantation had sufficient tissue integrity to support long term function in a human recipient. BACKGROUND: Kidney transplantation remains the best available treatment for patients with end-stage kidney disease. However, a shortage of available donor human kidneys prevents many patients from achieving the benefits of transplantation. Xenotransplantation is a potential solution to this shortage. Recent pre-clinical human studies have demonstrated kidneys from genetically modified pig donors can be transplanted without hyperacute rejection and capable of providing creatinine and other solute clearance. It is unknown whether the porcine kidneys would tolerate the relatively higher resting blood pressure in an adult human recipient compared to the pig donor or non-human primate (NHP) recipients used in translational studies. Furthermore, previous experience in NHPs raised concerns about the tissue integrity of the porcine ureter and post-xenotransplant growth of the porcine kidney. METHODS: Kidneys recovered from porcine donors with 10 gene edits were transplanted into decedent brain dead recipients who were not eligible for organ donation. Decedents underwent bilateral native nephrectomy prior to transplant and were followed for 3-7 days. Standard induction and maintenance immunosuppression was used as previously reported. Vital signs including blood pressure were recorded frequently. Kidney xenografts were assessed daily, serially biopsied, and were measured at implantation and study completion. RESULTS: Three decedents underwent successful xenotransplantation. Subcapsular hematomas developed requiring incision of the xenograft capsules to prevent Page kidney. Blood pressures were maintained in a physiologic range for adult humans (median arterial pressures (MAP) 108.5mmHg (Interquartile Range (IQR): 97-114mmHg), 74mmHg (IQR: 71-78mmHg), and 95mmHg (IQR: 88-99mmHg. respectively) and no bleeding complications or aneurysm formation was observed. Serial biopsies were taken from the xenografts without apparent loss of tissue integrity, despite the lack of a capsule. Ureteroneocystotomies remained intact without evidence of urine leak. Xenograft growth was observed, but plateaued, in 1 decedent with increased volume of the left and right xenografts by 25% and 26%, respectively, and in the context of human growth hormone levels consistently less <0.1 ng/ml and insulin-like growth factor 1 levels ranging from 34-50 ng/ml. CONCLUSIONS: The findings of this study suggest kidneys from 10-gene edited porcine donors have sufficient tissue integrity to tolerate xenotransplantation into a living human recipient. There was no evidence of anastomotic complications and the xenografts tolerated needle biopsy without issue. Xenograft growth occurred but plateaued by study end; further observation and investigation will be required to confirm this finding and elucidate underlying mechanisms.

Physiologic homeostasis after pig-to-human kidney xenotransplantation.

Demand for kidney grafts outpaces supply, limiting kidney transplantation as a treatment for kidney failure. Xenotransplantation has the potential to make kidney transplantation available to many more patients with kidney failure, but the ability of xenografts to support human physiologic homeostasis has not been established. A brain-dead adult decedent underwent bilateral native nephrectomies followed by 10 gene-edited (four gene knockouts, six human transgenes) pig-to-human xenotransplantation. Physiologic parameters and laboratory values were measured for seven days in a critical care setting. Data collection aimed to assess homeostasis by measuring components of the renin-angiotensin-aldosterone system, parathyroid hormone signaling, glomerular filtration rate, and markers of salt and water balance. Mean arterial blood pressure was maintained above 60 mmHg throughout. Pig kidneys secreted renin (post-operative day three to seven mean and standard deviation: 47.3 ± 9 pg/mL). Aldosterone and angiotensin II levels were present (post-operative day three to seven, 57.0 ± 8 pg/mL and 5.4 ± 4.3 pg/mL, respectively) despite plasma renin activity under 0.6 ng/mL/hr. Parathyroid hormone levels followed ionized calcium. Urine output down trended from 37 L to 6 L per day with 4.5 L of electrolyte free water loss on post-operative day six. Aquaporin 2 channels were detected in the apical surface of principal cells, supporting pig kidney response to human vasopressin. Serum creatinine down trended to 0.9 mg/dL by day seven. Glomerular filtration rate ranged 90-240 mL/min by creatinine clearance and single-dose inulin clearance. Thus, in a human decedent model, xenotransplantation of 10 gene-edited pig kidneys provided physiologic balance for seven days. Hence, our in-human study paves the way for future clinical study of pig-to-human kidney xenotransplantation in living persons.

A Current View of SARS-CoV-2 Vaccine Policies Amongst Pediatric Renal Transplant Centers and Relationships to State Policy.

Given its mortality benefit, renal transplantation remains the ideal treatment modality for end stage renal disease in children. Despite the recent expansion of use in young children, the novel SARS-CoV-2 vaccine has not been universally accepted. Similarly, vaccine related state regulations are heterogenous. We present a cross-sectional analysis of institutional specific vaccination policies at US pediatric renal transplant centers and relationships to state legislation. We found that 36.1% of institutions require COVID-19 vaccination prior to transplant, while 17 states have current legislation prohibiting proof of vaccination as a means of access to public services. Of the 63.9% of transplant centers without immunization requirement, almost two-thirds are located in states without prohibitory regulations. Despite an unclear primary influence of institutional policy, our study demonstrates a lack of standardization and potential to create unnecessary inequities.

An Online Survey and Focus Groups for Promoting Cancer Prevention Measures.

In order to design a cancer prevention promotion program in the region, suggestions were solicited at a medical center. We hypothesized that a majority would be native to state, and would be able to articulate about the barriers that may exist. Through online survey and focus groups, suggestions were sought, and the knowledge and the compliance with cancer prevention recommendations were assessed to determine the participants' qualifications as potential educators. Sixty-five point two percent of participants (n = 1018) graduated from high school in Arkansas. The most commonly given suggestions were to provide education to increase awareness, to use social media for promotion, to improve access, and to reduce costs. Self-reported adherence rates to breast, cervical, and colorectal cancer screening were 82.6% (n = 954), 75.8% (n = 541), and 76.7% (n = 453), respectively. Having a personal history of cancer significantly increased colorectal cancer screening uptake (p = 0.04), but paradoxically decreased mammography uptake (p = 0.007). Salary of $40,000 and more and having a Bachelor's degree or higher were associated with higher compliance of Papanicolaou test only (p = 0.007 and p = 0.001, respectively). A majority (67.7%, n = 1056) of respondents expressed willingness to contribute to promoting cancer prevention measures, and 38.3% (n = 559) were willing to participate in focus groups. However, only 6.3% (n = 35) actually participated. The participants' knowledge and compliance appeared to be sufficient, but their follow through in focus group participation was poor.