. R.A.D. has served on the advisory board and as a paid consultant for Ergo Science. A.H.C. is a member of the Board of Directors of Ergo Science and holds stock in that company.Abbreviations: CV, coefficient of variation; EGP, endogenous glucose production; FFA, free fatty acid; FFM, fat-free mass; FPG, fasting plasma glucose; GIR, exogenous glucose infusion rate; MRI, magnetic resonance imaging; OGTT, oral glucose tolerance test; R a , rate of endogenous glucose appearance.A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. BromocriptineA novel approach to the treatment of type 2 diabetesOBJECTIVE -In vertebrates, body fat stores and insulin action are controlled by the temporal interaction of circadian neuroendocrine oscillations. Bromocriptine modulates neurotransmitter action in the brain and has been shown to improve glucose tolerance and insulin resistance in animal models of obesity and diabetes. We studied the effect of a quick-release bromocriptine formulation on glucose homeostasis and insulin sensitivity in obese type 2 diabetic subjects.RESEARCH DESIGN AND METHODS -There were 22 obese subjects with type 2 diabetes randomized to receive a quick-release formulation of bromocriptine (n = 15) or placebo (n = 7) in a 16-week double-blind study. Subjects were prescribed a weight-maintaining diet to exclude any effect of changes in body weight on the primary outcome measurements. Fasting plasma glucose concentration and HbA 1c were measured at 2-to 4-week intervals during treatment. Body composition (underwater weighing), body fat distribution (magnetic resonance imaging), oral glucose tolerance (oral glucose tolerance test [OGTT]), insulin-mediated glucose disposal, and endogenous glucose production (2-step euglycemic insulin clamp, 40 and 160 mU и min Ϫ1 и m Ϫ2 ) were measured before and after treatment.RESULTS -No changes in body weight or body composition occurred during the study in either placebo-or bromocriptine-treated subjects. Bromocriptine significantly reduced HbA 1c (from 8.7 to 8.1%, P = 0.009) and fasting plasma glucose (from 190 to 172 mg/dl, P = 0.02) levels, whereas these variables increased during placebo treatment (from 8.5 to 9.1%, NS, and from 187 to 223 mg/dl, P = 0.02, respectively). The differences in HbA 1c (⌬ = 1.2%, P = 0.01) and fasting glucose (⌬ = 54 mg/dl, P Ͻ 0.001) levels between the bromocriptine and placebo group at 16 weeks were highly significant. The mean plasma glucose concentration during OGTT was significantly reduced by bromocriptine (from 294 to 272 mg/dl, P = 0.005), whereas it increased in the placebo group. No change in glucose disposal occurred during the first step of the insulin clamp in either the bromocriptine-or placebo-treated group. During the second insulin clamp step, bromocriptine improved total glucose disposal from 6.8 to 8.4 mg и min Ϫ1 и kg Ϫ1 fat-free mass (FFM) (P = 0.01) and nonoxidative glucose disposal from 3.3 to 4.3 mg и min Ϫ1 и kg Ϫ1 FFM (P Ͻ 0.05), whereas ...

A radical solution is needed for the organ supply crisis, and the domestic pig is a promising organ source. In preparation for a clinical trial of xenotransplantation, we developed an in vivo pre‐clinical human model to test safety and feasibility tenets established in animal models. After performance of a novel, prospective compatible crossmatch, we performed bilateral native nephrectomies in a human brain‐dead decedent and subsequently transplanted two kidneys from a pig genetically engineered for human xenotransplantation. The decedent was hemodynamically stable through reperfusion, and vascular integrity was maintained despite the exposure of the xenografts to human blood pressure. No hyperacute rejection was observed, and the kidneys remained viable until termination 74 h later. No chimerism or transmission of porcine retroviruses was detected. Longitudinal biopsies revealed thrombotic microangiopathy that did not progress in severity, without evidence of cellular rejection or deposition of antibody or complement proteins. Although the xenografts produced variable amounts of urine, creatinine clearance did not recover. Whether renal recovery was impacted by the milieu of brain death and/or microvascular injury remains unknown. In summary, our study suggests that major barriers to human xenotransplantation have been surmounted and identifies where new knowledge is needed to optimize xenotransplantation outcomes in humans.

Use of organs from donors testing positive for hepatitis B virus (HBV) may safely expand the donor pool. The American Society of Transplantation convened a multidisciplinary expert panel that reviewed the existing literature and developed consensus recommendations for recipient management following the use of organs from HBV positive donors. Transmission risk is highest with liver donors and significantly lower with non‐liver (kidney and thoracic) donors. Antiviral prophylaxis significantly reduces the rate of transmission to liver recipients from isolated HBV core antibody positive (anti‐HBc+) donors. Organs from anti‐HBc+ donors should be considered for all adult transplant candidates after an individualized assessment of the risks and benefits and appropriate patient consent. Indefinite antiviral prophylaxis is recommended in liver recipients with no immunity or vaccine immunity but not in liver recipients with natural immunity. Antiviral prophylaxis may be considered for up to 1 year in susceptible non‐liver recipients but is not recommended in immune non‐liver recipients. Although no longer the treatment of choice in patients with chronic HBV, lamivudine remains the most cost‐effective choice for prophylaxis in this setting. Hepatitis B immunoglobulin is not recommended.

APOL1 gene variants are associated with end-stage renal disease in African Americans. Here we investigate the impact of recipient APOL1 (apolipoprotein L-1) gene distributions on kidney allograft outcomes. We conducted a retrospective analysis of 119 African American kidney transplant recipients, and found that 58 (48.7%) carried two APOL1 kidney disease risk variants. Contrary to the association seen in native kidney disease, there is no difference in allograft survival at 5 years post-transplant for recipients with high-risk APOL1 genotypes. Thus, we were able to conclude that APOL1 genotypes do not increase risk of allograft loss after kidney transplantations, and carrying 2 APOL1 risk alleles should not be an impediment to transplantation.

Determining candidacy for live kidney donation among obese individuals remains challenging. Among healthy non-donors, body mass index (BMI) above 30 is associated with a 16% increase in risk of end-stage renal disease (ESRD). However, the impact on the ESRD risk attributable to donation and living with only one kidney remains unknown. Here we studied the risk of ESRD associated with obesity at the time of donation among 119 769 live kidney donors in the United States. Maximum follow-up was 20 years. Obese (BMI above 30) live kidney donors were more likely male, African American, and had higher blood pressure. Estimated risk of ESRD 20 years after donation was 93.9 per 10 000 for obese; significantly greater than the 39.7 per 10 000 for non-obese live kidney donors. Adjusted for age, sex, ethnicity, blood pressure, baseline estimated glomerular filtration rate , and relationship to recipient, obese live kidney donors had a significant 86% increased risk of ESRD compared to their non-obese counterparts (adjusted hazard ratio 1.86; 95% confidence interval 1.05–3.30). For each unit increase in BMI above 27kg/m2 there was an associated significant 7% increase in ESRD risk (1.07, 1.02–1.12). The impact of obesity on ESRD risk was similar for male and female donors, African American and Caucasian donors, and across the baseline estimated glomerular filtration rate spectrum. These findings may help to inform selection criteria and discussions with persons considering living kidney donation.

Introduction: The scope of the impact of the COVID-19 pandemic on living donor kidney transplantation (LDKT) practices is not well defined. Methods: We surveyed US transplant programs to assess practices, strategies, and barriers to living LDKT during the COVID-19 pandemic. After institutional review board approval, the survey was distributed from 9 May 2020 to 30 May 2020 by e-mail and postings to professional society list-servs. Responses were stratified based on state COVID-19 cumulative incidence levels. Results: Staff at 118 unique centers responded, representing 61% of US living donor recovery programs and 75% of LKDT volume in the prepandemic year. Overall, 66% reported that LDKT surgery was on hold (81% in "high" vs. 49% in "low" COVID-19 cumulative incidence states). A total of 36% reported that evaluation of new donor candidates had paused, 27% reported that evaluations were very much decreased (>0% to <25% typical), and 23% reported that evaluations were moderately decreased (25% to <50% typical). Barriers to LDKT surgery included program concerns for donor (85%) and recipient (75%) safety, patient concerns (56%), elective case restrictions (47%), and hospital administrative restrictions (48%). Programs with higher local COVID-19 cumulative incidence reported more barriers related to staff and resource diversion. Most centers continuing donor evaluations used remote strategies (video, 82%; telephone, 43%). As LDKT resumes, all programs will screen for COVID-19, although timeframe and modalities will vary. Recommendations for presurgical self-quarantine are also variable. Conclusion: The COVID-19 pandemic has had broad impacts on LDKT practice. Ongoing research and consensus building are needed to reduce barriers, to guide optimal practices, and to support safe restoration of LDKT across centers.

Young AAs were at highest risk for CKD, and APOL1 renal-risk variants drove some of this risk. Understanding the genetic profile of young AA potential living kidney donors in the context of baseline health characteristics may help to inform candidate selection and counseling.

Patients with ESKD who would benefit from a kidney transplant face a critical and continuing shortage of kidneys from deceased human donors. As a result, such patients wait a median of 3.9 years to receive a donor kidney, by which time approximately 35% of transplant candidates have died while waiting or have been removed from the waiting list. Those of blood group B or O may experience a significantly longer waiting period. This problem could be resolved if kidneys from genetically engineered pigs offered an alternative with an acceptable clinical outcome. Attempts to accomplish this have followed two major paths: deletion of pig xenoantigens, as well as insertion of “protective” human transgenes to counter the human immune response. Pigs with up to nine genetic manipulations are now available. In nonhuman primates, administering novel agents that block the CD40/CD154 costimulation pathway, such as an anti-CD40 mAb, suppresses the adaptive immune response, leading to pig kidney graft survival of many months without features of rejection (experiments were terminated for infectious complications). In the absence of innate and adaptive immune responses, the transplanted pig kidneys have generally displayed excellent function. A clinical trial is anticipated within 2 years. We suggest that it would be ethical to offer a pig kidney transplant to selected patients who have a life expectancy shorter than the time it would take for them to obtain a kidney from a deceased human donor. In the future, the pigs will also be genetically engineered to control the adaptive immune response, thus enabling exogenous immunosuppressive therapy to be significantly reduced or eliminated.