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.

Psychosocial Evaluation of Living Kidney Donors: A Survey of Current Practices in the United States.

BACKGROUND: Best practices in psychosocial evaluation and care of living donor candidates and donors are not well established. METHODS: We surveyed 195 living kidney donor (LKD) transplant centers in United States from October 2021 to April 2022 querying (1) composition of psychosocial teams, (2) evaluation processes including clinical tools and domains assessed, (3) selection criteria, and (4) psychosocial follow-up post-donation. RESULTS: We received 161 responses from 104 programs, representing 53% of active LKD programs and 67% of LKD transplant volume in 2019. Most respondents (63%) were social workers/independent living donor advocates. Over 90% of respondents indicated donor candidates with known mental health or substance use disorders were initially evaluated by the psychosocial team. Validated psychometric or transplant-specific tools were rarely utilized but domains assessed were consistent. Active suicidality, self-harm, and psychosis were considered absolute contraindications in >90% of programs. Active depression was absolute contraindication in 50% of programs; active anxiety disorder was excluded 27%. Conditions not contraindicated to donation include those in remission: anxiety (56%), depression (53%), and posttraumatic stress disorder (41%). There was acceptance of donor candidates using alcohol, tobacco, or cannabis recreationally, but not if pattern met criteria for active use disorder. Seventy-one percent of programs conducted post-donation psychosocial assessment and use local resources to support donors. CONCLUSIONS: There was variation in acceptance of donor candidates with mental health or substance use disorders. Although most programs conducted psychosocial screening post-donation, support is not standardized and unclear if adequate. Future studies are needed for consensus building among transplant centers to form guidelines for donor evaluation, acceptance, and support.

The impact of the OPTN policy change on patients with a durable left ventricular assist device and chronic kidney disease: Analysis of the UNOS database.

BACKGROUND: The Organ Procurement and Transplantation Network (OPTN) implemented modifications in 2018 to the adult heart transplant allocation system to better stratify the most medically urgent transplant candidates. We evaluated the impact of these changes on patients supported by a durable left ventricular assist device (LVAD) with chronic kidney disease (CKD). OBJECTIVE: To evaluate the impact of the OPTN policy change on patients supported by durable left ventricular assist devices (LVAD) with chronic kidney disease (CKD). METHODS: We performed an analysis of patients from the United Network of Organ Sharing Database supported by durable LVAD listed for a heart transplant (HT) between October 17, 2016 and September 30, 2021. Patients were divided into two groups: pre- and postpolicy, depending on whether they were listed on or prior to October 17, 2018. Patients who were on dialysis prior to surgery or discharge were excluded from the analysis. Patients with simultaneous heart and kidney transplants were excluded. Patients who were listed for transplant prepolicy change but transplanted postpolicy change were excluded. This cohort was then subdivided into degrees of CKD based on estimated glomerular filtration rate (eGFR), which resulted in 678 patients (23.7%) in Stage 1 (GFR ≥89.499) (Prepolicy: 345, Postpolicy: 333), 1233 (43.1%) in Stage 2 (89.499 > GFR ≥ 59.499) (Prepolicy: 618, Postpolicy: 615), 613 (21.4%) in Stage 3a (59.499 > GFR ≥ 44.499) (Prepolicy: 291, Postpolicy: 322), 294 (10.3%) in Stage 3b (44.499 > GFR ≥ 29.499) (Prepolicy: 143, Postpolicy: 151), 36 (1.3%) in Stage 4 (29.499 > GFR ≥ 15) (Prepolicy: 21, Postpolicy: 15), and 9 (0.3%) in Stage 5 (15 > GFR) (Prepolicy: 4, Postpolicy: 5). The primary outcome was 1-year and 2-year post-HT survival. RESULTS: There were 2863 patients who met the study criteria (1422 prepolicy, 1441 postpolicy). Overall survival, regardless of CKD stage, was lower following the policy change (p < 0.01). There was a similar risk of primary graft failure (PGF) in the pre- and postpolicy period (1.8% vs. 1.2%, p = 0.26). 1-year overall survival was 93% (91, 94) and 89% (87, 91) in the pre- and postpolicy periods, respectively. 2-year overall survival was 89% (88, 91) and 85% (82, 87) in the pre- and postpolicy periods, respectively. For CKD Stages 1, 2, 3a, 3b, 4, and 5, 1 -year survival was 93% (91, 95), 92% (90,93), 89% (86, 91), 89% (86, 93), 80% (68, 94), and 100% (100, 100), respectively. For CKD Stages 1, 2, 3a, 3b, 4, and 5, 2-year survival was 91% (88, 93), 88% (86, 90), 84% (81, 88), 84% (80, 89), 73% (59, 90), and 100% (100, 100), respectively. Patients with CKD 1 and 2 had better survival compared to those with CKD 3 (p < 0.01) and CKD 4 and 5 (p = 0.03) in the pre- and postpolicy periods. Patients with CKD 3 did not have a survival advantage over those with CKD 4 and 5 (p = 0.25). On cox regression analysis, advancing degrees of CKD were associated with an increased risk of mortality. CONCLUSIONS: Patients with LVAD support had decreased overall survival after the OPTN policy change. Patients with more advanced CKD had lower survival than patients without advanced CKD, though they were not impacted by the OPTN policy change.

Spatiotemporal immune atlas of a clinical-grade gene-edited pig-to-human kidney xenotransplant.

Pig-to-human xenotransplantation is rapidly approaching the clinical arena; however, it is unclear which immunomodulatory regimens will effectively control human immune responses to pig xenografts. Here, we transplant a gene-edited pig kidney into a brain-dead human recipient on pharmacologic immunosuppression and study the human immune response to the xenograft using spatial transcriptomics and single-cell RNA sequencing. Human immune cells are uncommon in the porcine kidney cortex early after xenotransplantation and consist of primarily myeloid cells. Both the porcine resident macrophages and human infiltrating macrophages express genes consistent with an alternatively activated, anti-inflammatory phenotype. No significant infiltration of human B or T cells into the porcine kidney xenograft is detectable. Altogether, these findings provide proof of concept that conventional pharmacologic immunosuppression may be able to restrict infiltration of human immune cells into the xenograft early after compatible pig-to-human kidney xenotransplantation.

Use of LCP-Tacrolimus (LCPT) in Kidney Transplantation: A Delphi Consensus Survey of Expert Clinicians.

BACKGROUND LCPT (Envarsus XR®) is a common once-daily, extended-release oral tacrolimus formulation used in kidney transplantation. However, there are minimal evidence-based recommendations regarding optimal dosing and treatment in the de novo and conversion settings. MATERIAL AND METHODS Using Delphi methodology, 12 kidney transplantation experts with LCPT experience reviewed available data to determine potential consensus topics. Key statements regarding LCPT use were generated and disseminated to the panel in an online Delphi survey. Statements were either accepted, revised, or rejected based on the level of consensus, perceived strength of evidence, and alignment with clinical practice. Consensus was defined a priori as ≥75% agreement. RESULTS Twenty-three statements were generated: 14 focused on de novo LCPT use and 9 on general administration or LCPT conversion use. After 2 rounds, consensus was achieved for 11/14 of the former and 7/9 of the latter statements. In a de novo setting, LCPT was recognized as a first-line option based on its safety and efficacy compared to immediate-release tacrolimus. In particular, African Americans and rapid metabolizer populations were identified as preferred for first-line LCPT therapy. In a conversion setting, full consensus was achieved for converting to LCPT to address neurological adverse effects related to immediate-release tacrolimus and for the time required (approximately 7 days) for steady-state LCPT trough levels to be reached. CONCLUSIONS When randomized clinical trials do not replicate current utilization patterns, the Delphi process can successfully generate consensus statements by expert clinicians to inform clinical decision-making for the use of LCPT in kidney transplant recipients.

Should Transplant Nephrology Pursue Recognition from the Accreditation Council for Graduate Medical Education (ACGME)?

Kidney transplant is not only the best treatment for patients with advanced kidney disease but it also reduces health care expenditure. The management of transplant patients is complex as they require special care by transplant nephrologists who have expertise in assessing transplant candidates, understand immunology and organ rejection, have familiarity with perioperative complications, and have the ability to manage the long-term effects of chronic immunosuppression. This skill set at the intersection of multiple disciplines necessitates additional training in Transplant Nephrology. Currently, there are more than 250,000 patients with a functioning kidney allograft and over 100,000 waitlisted patients awaiting kidney transplant, with a burgeoning number added to the kidney transplant wait list every year. In 2022, more than 40,000 patients were added to the kidney wait list and more than 25,000 received a kidney transplant. The Advancing American Kidney Health Initiative, passed in 2019, is aiming to double the number of kidney transplants by 2030 creating a need for additional transplant nephrologists to help care for them. Over the past decade, there has been a decline in the Nephrology-as well Transplant Nephrology-workforce due to a multitude of reasons. The American Society of Transplantation Kidney Pancreas Community of Practice created a workgroup to discuss the Transplant Nephrology workforce shortage. In this article, we discuss the scope of the problem and how the Accreditation Council for Graduate Medical Education recognition of Transplant Nephrology Fellowship could at least partly mitigate the Transplant Nephrology work force crisis.

Health Inequity in Likelihood and Time to Renal Recovery after Living Kidney Donation: Implications for Kidney Health in Black Americans.

BACKGROUND: Live donor kidney transplantation has been popularized to help mitigate the organ shortage crisis. At the time of living donor nephrectomy, living donors lose 50% of their kidney function or glomerular filtration rate (GFR). Studies have shown that in healthy living donors, the remaining kidney is able to adapt and recover 10% to 25% of postdonation lost GFR. GFR recovery is critical to long-term kidney health, particularly for Black Americans who disproportionately suffer from kidney disease with an incidence 2.5 times White Americans. To date, no study has examined whether health inequities in renal recovery postdonation exist. STUDY DESIGN: We retrospectively analyzed 100,121 living kidney donors reported to the Scientific Registry of Transplant Recipients between 1999 and 2021. We estimated GFR (eGFR) using the Chronic Kidney Disease Epidemiology Collaboration 2021 equation and predicted the likelihood (logistic regression) and time (Cox regression) to recovery of 60% and 75% predonation eGFR. Models adjusted for age, sex, race, BMI, and predonation eGFR. RESULTS: Black patients were 47% (adjusted odds ratio 0.53, 95% CI 0.50 to 0.56, p < 0.001) and 43% (adjusted odds ratio 0.57, 95% CI 0.54 to 0.60, p < 0.001) less likely to recover 60% and 75% of predonation eGFR, respectively, compared with their White counterparts. The hazard ratio for time to renal recovery of 60% and 75% of predonation eGFR was 22% (adjusted hazard ratio 0.78, 95% CI 0.76 to 0.80, p < 0.001) and 38% (adjusted hazard ratio 0.62, 95% CI 0.60 to 0.65, p < 0.001) lower, respectively, than White patients. CONCLUSIONS: Black living kidney donors were less likely to recover predonation eGFR, and time to renal recovery was significantly longer than their White counterparts. These data highlight the need for enhanced living kidney donor follow-up, particularly for Black living kidney donors who are at greatest future risk of end-stage kidney disease.

Determinants of pulmonary hypertension in patients with end-stage kidney disease and arteriovenous access.

BACKGROUND: Pulmonary Hypertension (PH) is a sequela of arteriovenous (AV) fistulas (AVF) or AV grafts (AVG) in patients with end-stage kidney disease (ESKD) due to the creation of shunt physiology and increased pulmonary blood flow. PH has been consistently associated with increased mortality but there is a paucity of data regarding management. RESEARCH QUESTION: The objective of this study was to identify risk factors and outcomes in patients who develop PH after AVF or AVG creation for hemodialysis access. METHODS: Using the United States Renal Data System, we identified all patients over age 18 initiated on dialysis from 2012-2019 who did not receive renal transplant. We identified a) the predictors of PH in patients with ESKD on hemodialysis; b) the independent mortality risk associated with development of PH. RESULTS: We identified 478,896 patients initiated on dialysis from 2012-2019 of whom 27,787 (5.8 %) had a diagnosis of PH. The median age was 65 (IQR: 55-74) years and 59.1 % were male. Reduced ejection fraction, any congestive heart failure, obstructive sleep apnea, and female sex were the strongest predictors of PH diagnosis. Both AVG and AVF were also associated with an increased rate of PH diagnosis compared to catheter-based dialysis (p < 0.001). PH portended a poor prognosis and was associated with significantly increased mortality (p < 0.001). CONCLUSIONS: Patients with AVF or AVG should be screened using echocardiography prior to creation and monitored with serial echocardiography for the development of PH, and if present, considered for revision of the AVA. This is also the first study to identify that AVG are a risk factor for PH in dialysis patients.

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.