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Kidney allotransplantation remains the preferred treatment for end-stage kidney disease, yet donor shortages limit its availability. Xenotransplantation using genetically modified porcine kidneys offers a promising alternative. Here, we report key physiological observations from the first-in-human porcine kidney xenograft over a 51 day postoperative follow-up period. The transplanted kidney maintained essential functions, including waste excretion, electrolyte regulation, and production of concentrated urine, while supporting blood pressure and sodium reabsorption despite reduced activation of the renin-angiotensin-aldosterone system. Sodium retention required diuretic therapy, and mild hypocalcemia and hyperphosphatemia occurred in the setting of pre-existing hypoparathyroidism. Markedly increased urinary uric acid excretion led to hypouricemia without evidence of urate nephropathy. This case demonstrates the ability of a porcine kidney to sustain vital metabolic functions in a living human, while highlighting areas for further research. These findings provide a foundation for optimizing post-transplant care and advancing xenotransplantation as a solution to the critical organ shortage. Kidney shortages limit treatment options for patients with end-stage kidney disease, prompting exploration of xenotransplantation. Here, the authors show that a genetically modified pig kidney sustained essential functions in a living human for 51 days, informing future clinical strategies.

Proteinuria is associated with worse allograft outcomes in kidney transplant recipients (KTRs) and treatment strategies are limited. We examined the outcomes of calcineurin inhibitor (CNI) to belatacept conversion in proteinuric KTRs. In a pilot phase II single-arm multicenter prospective trial, we recruited adult KTRs >6 months post-kidney transplantation with an estimated glomerular filtration rate (eGFR) ≥30 ml/min/1.73m and proteinuria >1 g/day. Patients were converted from CNI to belatacept. The primary outcome was a 25% reduction in proteinuria at 12 months. A total of 15 KTRs were recruited who had pre-conversion median (interquartile range) proteinuria of 1.8 (IQR 1.4 - 3.5) g/g and estimated glomerular filtration rate (eGFR) of 48 (IQR 32 - 52.5) ml/min/1.73m . At 12 months post-conversion, median proteinuria was 1.4 (IQR 0.4 - 2.2) g/g ( = 0.068) and eGFR was maintained at 43 (34 - 54.5) ml/min/1.73m . The primary outcome of at least a 25% reduction in proteinuria occurred in 53% (8/15) at 12 months. Abbreviated IBOX scores predicting 7-year graft survival were also stable at 1-year post-conversion compared to baseline. At extended follow-up at 5 years, both proteinuria and eGFR remained stable at 0.69 (0.24 - 2.15) g/g and 39 (31 - 57) ml/min/1.73m , respectively. CNI to belatacept conversion was associated with preserved allograft function in KTRs with significant proteinuria. These findings need to be confirmed in a larger randomized clinical trial. https://clinicaltrials.gov/,

Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1∶1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings. ClinicalTrials.gov NCT00548405.

Among patients with short bowel syndrome who commonly have kidney disease, kidney transplantation remains challenging. We describe the clinicopathologic course of a 59-year old man with short bowel syndrome secondary to Crohn’s disease who underwent a deceased donor kidney transplant that was complicated by recurrent acute kidney allograft injury due to volume depletion from diarrhea, ultimately requiring the placement of permanent intravenous access for daily volume expansion at home resulting in the recovery of allograft function. Teduglutide treatment at 1.8 years post-transplant led to a dramatic decrease in diarrhea. A literature review of similar cases yielded 18 patients who underwent 19 kidney transplants. Despite high rates of complications, at the time of last follow-up (median 2.1 years [0.04-7]), 94% of the patients were still alive and 89% had functioning allografts, with a median eGFR of 37.5 [14-122] ml/min/1.73m2. In conclusion, despite high rates of complications, kidney transplantation in patients with short bowel syndrome is associated with acceptable short- and midterm outcomes. Further, we report for the first time the effects of the glucagon-like peptide-2 analogue teduglutide for short bowel syndrome in a kidney transplant recipient.

Background Reactivation of BK polyomavirus (BKPyV) due to immunosuppression after renal transplantation can lead to allograft nephropathy (BKAN) or even allograft loss. Many transplant centers implement screening protocols in an attempt to detect BKPyV reactivation before progression to BKAN, although the frequency and duration of screening vary widely among centers. Methods The New England BK Consortium (NEBKCON), a collaboration of 12 transplant centers in the northeastern United States, has adopted a standard BKPyV screening protocol (screening monthly for the first 6 months followed by screening every 3 months until 2 years after transplantation). Participating members implemented this screening protocol at their centers, and later measured adherence to the protocol as part of a NEBKCON quality improvement project. This study retrospectively analyzes BKPyV-specific outcomes in association with adherence to this protocol. Results Six centers reported data on 472 subjects who received a renal transplant between January 2016 and December 2017. Adherence to the screening protocol during the first 12 months (7.1–76.7%, mean 56.1%) and 24 months (2.9–52.5%, mean 36.8%) after transplant varied between centers. Rates of BKPyV viremia (3.6–28.2%, mean 20.6%) as well as BKAN (0–4.5%, mean 3.2%) also varied among centers. Adherence to the screening protocol was associated with a decrease in the magnitude of the initial viral load detected (3.29 vs. 3.74 log10 copies/mL, P = 0.065), but was not associated with peak viral load (3.95 vs. 4.14 log10 copies/mL, P = 0.47), viremia duration (179 vs. 196 days, P = 0.74), or incidence of BKAN among viremic subjects (15.3 vs. 16.0%, P = 0.91). Conclusion Even with a uniform screening protocol for BKPyV in place, adherence to this protocol varied widely among centers. More research is needed to determine patient-level and center-level barriers to adherence, as well as to determine optimal screening practices to further reduce the incidence of BKAN. Disclosures All authors: No reported disclosures.

Rabbit antithymocyte globulin (ATG) is commonly used as an induction therapy in renal transplant recipients, but the ideal dosage in tacrolimus-based early steroid withdrawal protocols has not been established. The purpose of this pilot study was to determine the immunophenotyping and efficacy of lower dose ATG in low immunological-risk kidney transplant recipients. In this prospective study, 45 patients were randomized (1:1) to our standard dose ATG (total dose 3.75 mg/kg)(sATG) vs. lower dose 2.25 mg/kg (lowATG). All patients underwent early steroid withdrawal within 7 days. The primary end point was biopsy-proven acute rejection at 12 months. Prospective immunophenotyping of freshly isolated PBMCs was performed at baseline, 3, 6, 12 months post-transplant. The rate of acute rejection was 17% and 10% in the sATG and lowATG, respectively. Effector memory T cells, Tregs and recent thymic emigrants T cells had similar kinetics post-transplant in both groups. No statistically significant differences were found in graft survival, patient survival or infections between the two groups, though there was a non-significant increase in leukopenia (43%v s. 30%), CMV (8% vs. 0) and BK (4% vs. 0) infections in sATG group vs. lowATG. In sum, in low immunological risk kidney recipients undergoing steroid withdrawal, low dose ATG seems to be efficacious in preventing acute rejection and depleting T cells with potentially lower infectious complications. A larger study is warranted to confirm these findings. Trial Registration ClinicalTrials.gov NCT00548405

In rabbits, mast cells were shown to degranulate during passive anaphylaxis. However, disodium cromoglycate was ineffective in altering degranulation of mast cells during this reaction.Mast cells degranulated during a provocative ragweed test in a patient with ragweed hay fever, and disodium cromoglycate inhibited degranulation of mast cells in the nasal mucosa pretreated with disodium cromoglycate. [PUBLICATION ABSTRACT]

Abstract BACKGROUND As spine surgery becomes increasingly common in the elderly, frailty has been used to risk stratify these patients. The Hospital Frailty Risk Score (HFRS) is a novel method of assessing frailty using International Classification of Diseases, Tenth Revision (ICD-10) codes. However, HFRS utility has not been evaluated in spinal surgery. OBJECTIVE To assess the accuracy of HFRS in predicting adverse outcomes of surgical spine patients. METHODS Patients undergoing elective spine surgery at a single institution from 2008 to 2016 were reviewed, and those undergoing surgery for tumors, traumas, and infections were excluded. The HFRS was calculated for each patient, and rates of adverse events were calculated for low, medium, and high frailty cohorts. Predictive ability of the HFRS in a model containing other relevant variables for various outcomes was also calculated. RESULTS Intensive care unit (ICU) stays were more prevalent in high HFRS patients (66%) than medium (31%) or low (7%) HFRS patients. Similar results were found for nonhome discharges and 30-d readmission rates. Logistic regressions showed HFRS improved the accuracy of predicting ICU stays (area under the curve [AUC] = 0.87), nonhome discharges (AUC = 0.84), and total complications (AUC = 0.84). HFRS was less effective at improving predictions of 30-d readmission rates (AUC = 0.65) and emergency department visits (AUC = 0.60). CONCLUSION HFRS is a better predictor of length of stay (LOS), ICU stays, and nonhome discharges than readmission and may improve on modified frailty index in predicting LOS. Since ICU stays and nonhome discharges are the main drivers of cost variability in spine surgery, HFRS may be a valuable tool for cost prediction in this specialty.

Abstract Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) determines prereceptor metabolism and activation of glucocorticoids within peripheral tissues. Its dysregulation has been implicated in a wide array of metabolic diseases, leading to the development of selective 11β-HSD1 inhibitors. We examined the impact of the reversible competitive 11β-HSD1 inhibitor, AZD4017, on the metabolic profile in an overweight female cohort with idiopathic intracranial hypertension (IIH). Methods We conducted a UK multicenter phase II randomized, double-blind, placebo-controlled trial of 12-week treatment with AZD4017. Serum markers of glucose homeostasis, lipid metabolism, renal and hepatic function, inflammation and androgen profiles were determined and examined in relation to changes in fat and lean mass by dual-energy X-ray absorptiometry. Results Patients receiving AZD4017 showed significant improvements in lipid profiles (decreased cholesterol, increased high-density lipoprotein [HDL] and cholesterol/HDL ratio), markers of hepatic function (decreased alkaline phosphatase and gamma-glutamyl transferase), and increased lean muscle mass (1.8%, P < .001). No changes in body mass index, fat mass, and markers of glucose metabolism or inflammation were observed. Patients receiving AZD4017 demonstrated increased levels of circulating androgens, positively correlated with changes in total lean muscle mass. Conclusions These beneficial metabolic changes represent a reduction in risk factors associated with raised intracranial pressure and represent further beneficial therapeutic outcomes of 11β-HSD1 inhibition by AZD4017 in this overweight IIH cohort. In particular, beneficial changes in lean muscle mass associated with AZD4017 may reflect new applications for this nature of inhibitor in the management of conditions such as sarcopenia.