Results of Two Cases of Pig-to-Human Kidney Xenotransplantation.

BACKGROUND: Xenografts from genetically modified pigs have become one of the most promising solutions to the dearth of human organs available for transplantation. The challenge in this model has been hyperacute rejection. To avoid this, pigs have been bred with a knockout of the alpha-1,3-galactosyltransferase gene and with subcapsular autologous thymic tissue. METHODS: We transplanted kidneys from these genetically modified pigs into two brain-dead human recipients whose circulatory and respiratory activity was maintained on ventilators for the duration of the study. We performed serial biopsies and monitored the urine output and kinetic estimated glomerular filtration rate (eGFR) to assess renal function and xenograft rejection. RESULTS: The xenograft in both recipients began to make urine within moments after reperfusion. Over the 54-hour study, the kinetic eGFR increased from 23 ml per minute per 1.73 m2 of body-surface area before transplantation to 62 ml per minute per 1.73 m2 after transplantation in Recipient 1 and from 55 to 109 ml per minute per 1.73 m2 in Recipient 2. In both recipients, the creatinine level, which had been at a steady state, decreased after implantation of the xenograft, from 1.97 to 0.82 mg per deciliter in Recipient 1 and from 1.10 to 0.57 mg per deciliter in Recipient 2. The transplanted kidneys remained pink and well-perfused, continuing to make urine throughout the study. Biopsies that were performed at 6, 24, 48, and 54 hours revealed no signs of hyperacute or antibody-mediated rejection. Hourly urine output with the xenograft was more than double the output with the native kidneys. CONCLUSIONS: Genetically modified kidney xenografts from pigs remained viable and functioning in brain-dead human recipients for 54 hours, without signs of hyperacute rejection. (Funded by Lung Biotechnology.).

A2/A2B to B deceased donor kidney transplantation in the Kidney Allocation System era.

Kidney transplantation from blood type A2/A2B donors to type B recipients (A2→B) has increased dramatically under the current Kidney Allocation System (KAS). Among living donor transplant recipients, A2-incompatible transplants are associated with an increased risk of all-cause and death-censored graft failure. In light of this, we used data from the Scientific Registry of Transplant Recipients from December 2014 until June 2022 to evaluate the association between A2→B listing and time to deceased donor kidney transplantation (DDKT) and post-DDKT outcomes for A2→B recipients. Among 53 409 type B waitlist registrants, only 12.6% were listed as eligible to accept A2→B offers ("A2-eligible"). The rates of DDKT at 1-, 3-, and 5-years were 32.1%, 61.4%, and 72.1% among A2-eligible candidates and 14.1%, 29.9%, and 44.1% among A2-ineligible candidates, with the former experiencing a 133% higher rate of DDKT (Cox weighted hazard ratio (wHR) = 2.192.332.47; P < .001). The 7-year adjusted mortality was comparable between A2→B and B-ABOc (type B/O donors to B recipients) recipients (wHR 0.780.941.13, P = .5). Moreover, there was no difference between A2→B vs B-ABOc DDKT recipients with regards to death-censored graft failure (wHR 0.771.001.29, P > .9) or all-cause graft loss (wHR 0.820.961.12, P = .6). Following its broader adoption since the implementation of the kidney allocation system, A2→B DDKT appears to be a safe and effective transplant modality for eligible candidates. As such, A2→B listing for eligible type B candidates should be expanded.

Single center utilization and post-transplant outcomes of thoracoabdominal normothermic regional perfusion deceased cardiac donor organs.

INTRODUCTION: Thoracoabdominal normothermic regional perfusion (TA-NRP) following cardiac death is an emerging multivisceral organ procurement technique. Recent national studies on outcomes of presumptive TA-NRP-procured organs are limited by potential misclassification since TA-NRP is not differentiated from donation after cardiac death (DCD) in registry data. METHODS: We studied 22 donors whose designees consented to TA-NRP and organ procurement performed at our institution between January 20, 2020 and July 3, 2022. We identified these donors in SRTR to describe organ utilization and recipient outcomes and compared them to recipients of traditional DCD (tDCD) and donation after brain death (DBD) organs during the same timeframe. RESULTS: All 22 donors progressed to cardiac arrest and underwent TA-NRP followed by heart, lung, kidney, and/or liver procurement. Median donor age was 41 years, 55% had anoxic brain injury, 45% were hypertensive, 0% were diabetic, and median kidney donor profile index was 40%. TA-NRP utilization was high across all organ types (88%-100%), with a higher percentage of kidneys procured via TA-NRP compared to tDCD (88% vs. 72%, p = .02). Recipient and graft survival ranged from 89% to 100% and were comparable to tDCD and DBD recipients (p ≥ .2). Delayed graft function was lower for kidneys procured from TA-NRP compared to tDCD donors (27% vs. 44%, p = .045). CONCLUSION: Procurement from TA-NRP donors yielded high organ utilization, with outcomes comparable to tDCD and DBD recipients across organ types. Further large-scale study of TA-NRP donors, facilitated by its capture in the national registry, will be critical to fully understand its impact as an organ procurement technique.

Single-port robotic-assisted ureteral reconstruction for management of strictures after renal transplantation.

Ureteral strictures are a common and often challenging complication of renal transplantation. The use of single-port (SP) robotic-assisted laparoscopic surgery is a novel approach in the management of these patients. Here we describe 3 patients with stricture of the transplant ureter causing hydronephrosis and allograft dysfunction, whose ureteral reconstructions were successfully performed using the SP robotic-assisted laparoscopic approach. Two patients underwent transplant-to-native ureteroureterostomy and 1 patient underwent ureteroneocystostomy. We demonstrate that the use of concurrent ureteroscopy and near-infrared fluorescence enables safe and rapid identification of native and transplant ureters. In addition, side-to-side anastomosis of transplant-to-native ureters allows for preservation of ureteral vasculature. In this limited series, the SP robotic platform demonstrates great promise in simplifying and streamlining our approach to ureteral strictures in this patient population.

External Validation of Toulouse-Rangueil eGFR12 Prediction Model After Living Donor Nephrectomy.

Decreased postdonation eGFR is associated with a higher risk of ESRD after living kidney donation, even when accounting for predonation characteristics. The Toulouse-Rangueil model (TRM) estimates 12 month postdonation eGFR (eGFR12) to inform counseling of candidates for living donation. The TRM was validated in several single-center European cohorts but has not been validated in US donors. We assessed the TRM in living kidney donors in the US using SRTR data 1/2000-6/2021. We compared the 2021 CKD-EPI equation eGFR12 observed estimates to the TRM eGFR12 predictions. Median (IQR) bias was -3.4 (-9.3, 3.4) mL/min/1.73 m2. Bias was higher for males vs. females (bias [IQR] -4.4 [-9.9, 1.8] vs. -2.9 [-8.8, 4.1]) and younger (31-40) vs. older donors (>50) (bias -4.9 [-10.6, 3.0] vs. -2.1 [-7.5, 4.0]). Bias was also larger for Black vs. White donors (bias (-6.7 [-12.1, -0.3], p < 0.001) vs. (-3.4 [-9.1, 3.1], p < 0.001)). Overall correlation was 0.71. In a sensitivity analysis using the 2009 CKD-EPI equation, results were generally consistent with exception to a higher overall bias (bias -4.2 [-9.8, 2.4]). The TRM overestimates postdonation renal function among US donors. Overestimation was greatest for those at higher risk for postdonation ESRD including male, Black, and younger donors. A new equation is needed to estimate postdonation renal function.

Immune response, phenotyping and molecular graft surveillance in kidney transplant recipients following severe acute respiratory syndrome coronavirus 2 vaccination.

BACKGROUND: Understanding immunogenicity and alloimmune risk following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in kidney transplant recipients is imperative to understanding the correlates of protection and to inform clinical guidelines. METHODS: We studied 50 kidney transplant recipients following SARS-CoV-2 vaccination and quantified their anti-spike protein antibody, donor-derived cell-free DNA (dd-cfDNA), gene expression profiling (GEP), and alloantibody formation. RESULTS: Participants were stratified using nucleocapsid testing as either SARS-CoV-2-naïve or experienced prior to vaccination. One of 34 (3%) SARS-CoV-2 naïve participants developed anti-spike protein antibodies. In contrast, the odds ratio for the association of a prior history of SARS-CoV-2 infection with vaccine response was 18.3 (95% confidence interval 3.2, 105.0, p < 0.01). Pre- and post-vaccination levels did not change for median dd-cfDNA (0.23% vs. 0.21% respectively, p = 0.13), GEP scores (9.85 vs. 10.4 respectively, p = 0.45), calculated panel reactive antibody, de-novo donor specific antibody status, or estimated glomerular filtration rate. CONCLUSIONS: SARS-CoV-2 vaccines do not appear to trigger alloimmunity in kidney transplant recipients. The degree of vaccine immunogenicity was associated most strongly with a prior history of SARS-CoV-2 infection.

A Randomized Double-Blinded Placebo Controlled Trial of Clazakizumab for the Treatment of COVID-19 Pneumonia With Hyperinflammation.

OBJECTIVES: We designed this study to test whether clazakizumab, a direct interleukin-6 inhibitor, benefits patients hospitalized with severe or critical COVID-19 disease accompanied by hyperinflammation. DESIGN: Multicenter, randomized, double-blinded, placebo-controlled, seamless phase II/III trial. SETTING: Five U.S. medical centers. PATIENTS: Adults inpatients with severe COVID-19 disease and hyperinflammation. INTERVENTIONS: Eighty-one patients enrolled in phase II, randomized 1:1:1 to low-dose (12.5 mg) or high-dose (25 mg) clazakizumab or placebo. Ninety-seven patients enrolled in phase III, randomized 1:1 to high-dose clazakizumab or placebo. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 28-day ventilator-free survival. Secondary outcomes included overall survival, frequency and duration of intubation, and frequency and duration of ICU admission. Per Data Safety and Monitoring Board recommendations, additional secondary outcomes describing clinical status and status changes, as measured by an ordinal scale, were added. Bayesian cumulative proportional odds, logistic, and Poisson regression models were used. The low-dose arm was dropped when the phase II study suggested superiority of the high-dose arm. We report on 152 patients, 74 randomized to placebo and 78 to high-dose clazakizumab. Patients receiving clazakizumab had greater odds of 28-day ventilator-free survival (odds ratio [OR] = 3.84; p [OR > 1] 99.9%), as well as overall survival at 28 and 60 days (OR = 1.75; p [OR > 1] 86.5% and OR = 2.53; p [OR > 1] 97.7%). Clazakizumab was associated with lower odds of intubation (OR = 0.2; p [OR] < 1; 99.9%) and ICU admission (OR = 0.26; p [OR < 1] 99.6%); shorter durations of ventilation and ICU stay (risk ratio [RR] < 0.75; p [RR < 1] > 99% for both); and greater odds of improved clinical status at 14, 28, and 60 days (OR = 2.32, p [OR > 1] 98.1%; OR = 3.36, p [OR > 1] 99.6%; and OR = 3.52, p [OR > 1] 99.8%, respectively). CONCLUSIONS: Clazakizumab significantly improved 28-day ventilator-free survival, 28- and 60-day overall survival, as well as clinical outcomes in hospitalized patients with COVID-19 and hyperinflammation.

One-year immunologic outcomes of lung transplantation utilizing hepatitis C-viremic donors.

Little is known about the effects of hepatitis C viremia on immunologic outcomes in the era of direct-acting antivirals. We conducted a prospective, single-arm trial of lung transplantation from hepatitis C-infected donors into hepatitis C-naïve recipients (n = 21). Recipients were initiated on glecaprevir-pibrentasvir immediately post-transplant and were continued on therapy for a total of 8 weeks. A control group of recipients of hepatitis C-negative lungs were matched 1:1 on baseline variables (n = 21). The primary outcome was the frequency of acute cellular rejection over 1-year post-transplant. Treatment with glecaprevir-pibrentasvir was well tolerated and resulted in viremia clearance after a median of 16 days of therapy (IQR 10-24 days). At one year, there was no difference in incidence of acute cellular rejection (71.4% vs. 85.7%, P = .17) or rejection requiring treatment (33.3% vs. 57.1%, P = .12). Mean cumulative acute rejection scores were similar between groups (.46 [SD ± .53] vs. .52 [SD ± .37], P = .67). Receipt of HCV+ organs was not associated with acute rejection on unadjusted Cox regression analysis (HR .55, 95% CI .28-1.11, P = .09), or when adjusted for risk factors known to be associated with acute rejection (HR .57, 95% CI .27-1.21, P = .14). Utilization of hepatitis C infected lungs with immediate treatment leads to equivalent immunologic outcomes at 1 year.

Caregiver exposure to hepatitis C virus following transplantation with hepatitis C viremic donor organs: A case series.

Direct-acting antiviral (DAA) therapeutics have ushered in an era in which transplanting organs from donors infected with hepatitis C virus (HCV+) into recipients without (HCV-) is an increasingly common practice. Rare but potentially life-threatening events have been reported in recipients of HCV+ organs. Since 2018 at our institution, 182 HCV- patients have received HCV+ donor organs. Here, we retrospectively reviewed cases in which recipients' family member caregivers reported sustaining needlestick exposures at home following discharge of the transplant recipient from the hospital. Caregiver needlestick exposures were passively reported in three cases of HCV+ into HCV- transplants (1.64% of such cases at our center). In all instances, the exposed individuals were aiding in diabetic management and the exposure occurred via lancets or insulin needles. In one case, the recipient viral load was undetectable at the time of the exposure but in the other two, recipients were viremic, putting their family members at risk to contract HCV infection. Surveillance for the exposed individuals was undertaken and no transmissions occurred. For centers performing HCV+ into HCV- transplants, it is important that informed consent includes discussion of potential secondary risks to family members and caregivers. Further, protocols for postexposure surveillance and for the acquisition of DAA treatment in the event of a secondary transmission should be in place.

Safety and Efficacy of Drug Eluting Stents for Treatment of Transplant Renal Artery Stenosis.

BACKGROUND: Transplant renal artery stenosis (TRAS) after renal transplantation is a common cause of graft dysfunction and failure. Endovascular intervention in the form of percutaneous transluminal angioplasty (PTA) and stenting has rapidly become the dominant treatment modality for the TRAS. There is a paucity of clinical data on the use of drug-eluting stent (DES) for TRAS. We investigated the outcomes of patients with clinically significant TRAS undergoing DES placement. METHODS: A retrospective review of patients with clinically significant TRAS undergoing PTA with DES placement from June 2014 to April 2021 was conducted. Patients treated for TRAS exhibited uncontrolled hypertension and/or unexplained allograft dysfunction. Patient demographics, procedural details, and follow-up outcomes were collected. Primary endpoints were the in-stent primary patency and graft survival. Secondary endpoints were freedom from reintervention, primary-assisted patency, and access-related complications. RESULTS: Thirteen TRAS in 12 patients with graft function alteration were treated with DES. The median age was 57 years (interquartile range (IQR), 48-63 years), and 9 (70%) patients were male. The median follow-up was 9 months (IQR, 4-52 months). The most common comorbidity was hypertension (100%), coronary artery disease (83%), and diabetes. The median time from deceased donor transplant to intervention was 5.8 months (IQR, 3.5-6.7 months). TRAS was most commonly found at the juxta-ostial segment (77%). The procedure was performed with carbon dioxide angiography with minimal amount of iodinated contrast (median, 3 mL) under local anesthesia in 9 (69%), and general anesthesia in 4 (31%) patients. The median stent diameter was 4.5 mm (IQR, 4-5 mm), and the median stent length was 15 mm (IQR, 15-18 mm). No intraoperative complications occurred. The rates of stenosis-free primary patency of the DES and graft survival were 76% and 100%, respectively. All 3 reinterventions for restenosis resulted from the kinking of the transplant renal artery proximal to the DES, which were treated by extending the stent more proximally 1-2 mm into the external iliac artery. There were no access-related complications. The median time to reintervention was 0.9 months (range, 0.23-2 months). Freedom from reintervention and primary-assisted patency were 76% and 100%, respectively. CONCLUSIONS: Our study demonstrates that DES is a safe and effective treatment modality in patients with TRAS at short to mid-term follow-up. As all reinterventions after DES were performed due to kinking of the transplant renal artery proximal to the stent, bridging of the DES 1-2 mm into the external iliac artery is recommended.

Pancreas transplantation from hepatitis C viremic donors to uninfected recipients.

Despite utilization of hepatitis C viremic organs for hepatitis C naïve recipients (HCV D+/R-) in other solid organ transplants, HCV viremic pancreata remain an unexplored source of donor organs. This study reports the first series of HCV D+/R- pancreas transplants. HCV D+/R- had shorter waitlist times compared to HCV D-/R-, waiting a mean of 16 days from listing for HCV-positive organs. HCV D+/R- had a lower match allocation sequence than HCV D-/R-, and this correlated with receipt of organs with a lower Pancreas Donor Risk Index (PDRI) score. All HCV D+/R- had excellent graft function with a mean follow-up of 438 days and had undetectable HCV RNA levels by a mean of 23 days after initiation of HCV-directed therapy. The rates of infectious complications, reoperation, readmission, rejection, and length of stay were not impacted by donor HCV status. A national review of potential ideal pancreas donors found that 37% of ideal HCV-negative pancreas allografts were transplanted, compared to only 5% of ideal HCV-positive pancreas allografts. The results of the current study demonstrate the safety of accepting HCV-positive pancreata for HCV-naïve recipients and advocates for increased utilization of ideal HCV-positive pancreas allografts.

Outcomes at 3 years posttransplant in imlifidase-desensitized kidney transplant patients.

Imlifidase is a cysteine proteinase which specifically cleaves IgG, inhibiting Fc-mediated effector function within hours of administration. Imlifidase converts a positive crossmatch to a potential donor (T cell, B cell, or both), to negative, enabling transplantation to occur between previously HLA incompatible donor-recipient pairs. To date, 39 crossmatch positive patients received imlifidase prior to a kidney transplant in four single-arm, open-label, phase 2 studies. At 3 years, for patients who were AMR+ compared to AMR-, death-censored allograft survival was 93% vs 77%, patient survival was 85% vs 94%, and mean eGFR was 49 ml/min/1.73 m2 vs 61 ml/min/1.73 m2 , respectively. The incidence of AMR was 38% with most episodes occurring within the first month post-transplantation. Sub-analysis of patients deemed highly sensitized with cPRA ≥ 99.9%, and unlikely to be transplanted who received crossmatch-positive, deceased donor transplants had similar rates of patient survival, graft survival, and eGFR but a higher rate of AMR. These data demonstrate that outcomes and safety up to 3 years in recipients of imlifidase-enabled allografts is comparable to outcomes in other highly sensitized patients undergoing HLA-incompatible transplantation. Thus, imlifidase is a potent option to facilitate transplantation among patients who have a significant immunologic barrier to successful kidney transplantation. Clinical Trial: ClinicalTrials.gov (NCT02790437), EudraCT Number: 2016-002064-13.

Quantifying infection risks in incompatible living donor kidney transplant recipients.

Desensitization has enabled incompatible living donor kidney transplantation (ILDKT) across HLA/ABO barriers, but added immunomodulation might put patients at increased risk of infections. We studied 475 recipients from our center from 2010 to 2015, categorized by desensitization intensity: none/compatible (n = 260), low (0-4 plasmaphereses, n = 47), moderate (5-9, n = 74), and high (≥10, n = 94). The 1-year cumulative incidence of infection was 50.1%, 49.8%, 66.0%, and 73.5% for recipients who received none, low, moderate, and high-intensity desensitization (P < .001). The most common infections were UTI (33.5% of ILDKT vs. 21.5% compatible), opportunistic (21.9% vs. 10.8%), and bloodstream (19.1% vs. 5.4%) (P < .001). In weighted models, a trend toward increased risk was seen in low (wIRR = 0.77 1.402.56 ,P = .3) and moderately (wIRR = 0.88 1.352.06 ,P = .2) desensitized recipients, with a statistically significant 2.22-fold (wIRR = 1.33 2.223.72 ,P = .002) increased risk in highly desensitized recipients. Recipients with ≥4 infections were at higher risk of prolonged hospitalization (wIRR = 2.62 3.574.88 , P < .001) and death-censored graft loss (wHR = 1.15 4.0113.95 ,P = .03). Post-KT infections are more common in desensitized ILDKT recipients. A subset of highly desensitized patients is at ultra-high risk for infections. Strategies should be designed to protect patients from the morbidity of recurrent infections, and to extend the survival benefit of ILDKT across the spectrum of recipients.

Impact of the 2014 kidney allocation system changes on trends in A2/A2B into B kidney transplantation and organ procurement organization reporting of donor subtyping.

The current kidney allocation system (KAS) preferentially allocates kidneys from blood type A2 or A2B (A/A2B) donors to blood type B candidates. We used national data to evaluate center-level performance of A2/A2B to B transplants, and organ procurement organization (OPO) reporting of type A or AB donor subtyping, in 5-year time periods prior to (2009-2014) and following (2015-2019) KAS implementation. The number of centers performing A2/A2B to B transplants increased from 17 pre-KAS to 76 post-KAS, though this still represents only a minority of centers (7.3% pre-KAS and 32.6% post-KAS). For high-performing centers, the median net increase in A2/A2B to B transplants was 19 cases (range -2-72) per center in the 5 years post-KAS. The median net increase in total B recipient transplants was 21 cases (range -17-119) per center. Despite requirements for performance of subtyping, in 2019 subtyping was reported on only 56.4% of A/AB donors. This translates into potential missed opportunities for B recipients, and even post-KAS up to 2322 A2/A2B donor kidneys may have been allocated for transplantation as A/AB. Further progress must be made both at center and OPO levels to broaden implementation of A2/A2B to B transplants for the benefit of underserved recipients.

Mitochondrial membrane potential and delayed graft function following kidney transplantation.

Delayed graft function (DGF) complicates 20%-40% of deceased-donor kidney transplants and is associated with increased length of stay and subsequent allograft failure. Accurate prediction of DGF risk for a particular allograft could influence organ allocation, patient counseling, and postoperative planning. Mitochondrial dysfunction, a reported surrogate of tissue health in ischemia-perfusion injury, might also be a surrogate for tissue health after organ transplantation. To understand the potential of mitochondrial membrane potential (MMP) in clinical decision-making, we analyzed whether lower MMP, a measure of mitochondrial dysfunction, was associated with DGF. In a prospective, single-center proof-of-concept study, we measured pretransplant MMP in 28 deceased donor kidneys and analyzed the association between MMP and DGF. We used hybrid registry-augmented regression to adjust for donor and recipient characteristics, minimizing overfitting by leveraging Scientific Registry of Transplant Recipients data. The range of MMP levels was 964-28 333 units. Low-MMP kidneys (MMP<4000) were more likely from female donors (75% vs 10%, P = .002) and donation after cardiac death donors (75% vs 12%, P = .004). For every 10% decrease in MMP levels, there were 38% higher odds of DGF (adjusted odds ratio = 1.08 1.381.78 , P = .01). In summary, MMP might be a promising pretransplant surrogate for tissue health in kidney transplantation and, after further validation, could improve clinical decision-making through its independent association with DGF.

Early airway dehiscence: Risk factors and outcomes with the rising incidence of extracorporeal membrane oxygenation as a bridge to lung transplantation.

BACKGROUND: Anastomotic complications occur in 7% to 18% of lung transplant recipients, among which airway dehiscence (AD) is particularly catastrophic. Using multi-institutional registry data, this study compared preoperative recipient/donor risk factors and outcomes in patients with and without AD and analyzed the effect of extracorporeal membrane oxygenation (ECMO) on the incidence of AD. METHODS: Data on adult lung transplants from 2007 to 2017 were provided by the Scientific Registry of Transplant Recipients. Patients receiving isolated lobar transplantation and patients with unknown AD status were excluded. Multivariable logistic regression identified independent risk factors for AD. Kaplan-Meier curves and log-rank tests describe mortality and graft survival. RESULTS: Of 18 122 lung transplants, 275 (1.5%) experienced AD. While the incidence of ECMO steadily increased from 0.7% to 5.9% over the study period, the incidence of AD remained relatively constant. Multivariable analysis revealed recipient male gender and prolonged ( > 48 hours) posttransplant mechanical ventilation as independent predictive factors for AD, while advanced donor age and single left lung transplant were protective factors. Recipient chronic steroid use, recipient diabetes, donor diabetes, and donor smoking history were not predictive of AD. Mortality and graft failure were significantly worse in the AD group. CONCLUSIONS: Despite increased ECMO utilization, the incidence of AD has remained stable. Multiple independent risk factors for AD were identified and poor postoperative outcomes confirmed. However, many known impediments to wound healing such as recipient chronic steroid use, recipient and donor diabetes, and donor smoking were not identified as risk factors for AD, reinforcing the critical role of technical performance.

IdeS (Imlifidase): A Novel Agent That Cleaves Human IgG and Permits Successful Kidney Transplantation Across High-strength Donor-specific Antibody.

OBJECTIVES: The presence of a donor-specific positive crossmatch has been considered to be a contraindication to kidney transplantation because of the risk of hyperacute rejection. Desensitization is the process of removing hazardous preformed donor-specific antibody (DSA) in order to safely proceed with transplant. Traditionally, this involves plasmapheresis and intravenous immune globulin treatments that occur over days to weeks, and has been feasible when there is a living donor and the date of the transplant is known, allowing time for pre-emptive treatments. For sensitized patients without a living donor, transplantation has been historically difficult. SUMMARY OF BACKGROUND DATA: IdeS (imlifidase) is an endopeptidase derived from Streptococcus pyogenes which has specificity for human IgG, and when infused intravenously results in rapid cleavage of IgG. METHODS: Here we present our single-center's experience with 7 highly sensitized (cPRA98-100%) kidney transplant candidates who had DSA resulting in positive crossmatches with their donors (5 deceased, 2 living) who received IdeS within 24 hours prior to transplant. RESULTS: All pre-IdeS crossmatches were positive and would have been prohibitive for transplantation. All crossmatches became negative post-IdeS and the patients underwent successful transplantation. Three patients had DSA rebound and antibody-mediated rejection, which responded to standard of care therapies. Three patients had delayed graft function, which ultimately resolved. No serious adverse events were associated with IdeS. All patients have functioning renal allografts at a median follow-up of 235 days. CONCLUSION: IdeS may represent a groundbreaking new method of desensitization for patients who otherwise might have no hope for receiving a lifesaving transplant.

The prognostic value of the furosemide stress test in predicting delayed graft function following deceased donor kidney transplantation.

OBJECTIVES AND METHODS: The Furosemide Stress Test (FST) is a novel dynamic assessment of tubular function that has been shown in preliminary studies to predict patients who will progress to advanced stage acute kidney injury, including those who receive renal replacement therapy (RRT). The aim of this study is to investigate if the urinary response to a single intraoperative dose of intravenous furosemide predicts delayed graft function (DGF) in patients undergoing deceased donor kidney transplant. RESULTS: On an adjusted multiple logistic regression, a single 100 mg dose of intraoperative furosemide after the anastomosis of the renal vessels (FST) predicted the need for RRT at 2 and 6 h post kidney transplantation (KT). Recipient urinary output was measured at 2 and 6 h post furosemide administration. In receiver-operating characteristic (ROC) analysis, the FST predicted DGF with an area-under-the curve of 0.85 at an optimal urinary output cut-off of <600 mls at 6 h with a sensitivity of and a specificity of 83% and 74%, respectively. CONCLUSIONS: The FST is a predictor of DGF post kidney transplant and has the potential to identify patients requiring RRT early after KT.

Frailty, Length of Stay, and Mortality in Kidney Transplant Recipients: A National Registry and Prospective Cohort Study.

OBJECTIVE: To test whether frailty, a novel measure of physiologic reserve, is associated with longer kidney transplant (KT) length of stay (LOS), and modifies the association between LOS and mortality. BACKGROUND: Better understanding of LOS is necessary for informed consent and discharge planning. Mortality resulting from longer LOS has important regulatory implications for hospital and transplant programs. Which recipients are at risk of prolonged LOS and its effect on mortality are unclear. Frailty is a novel preoperative predictor of poor KT outcomes including delayed graft function, early hospital readmission, immunosuppression intolerance, and mortality. METHODS: We used registry-augmented hybrid methods, a novel approach to risk adjustment, to adjust for LOS risk factors from the Scientific Registry of Transplant Recipients (n = 74,859) and tested whether (1) frailty, measured immediately before KT in a novel cohort (n = 589), was associated with LOS (LOS: negative binomial regression; LOS ≥2 weeks: logistic regression) and (2) whether frailty modified the association between LOS and mortality (interaction term analysis). RESULTS: Frailty was independently associated with longer LOS [relative risk = 1.15, 95% confidence interval (CI): 1.03-1.29; P = 0.01] and LOS ≥2 weeks (odds ratio = 1.57, 95% CI: 1.06-2.33; P = 0.03) after accounting for registry-based risk factors, including delayed graft function. Frailty also attenuated the association between LOS and mortality (nonfrail hazard rate = 1.55 95% CI: 1.30-1.86; P < 0.001; frail hazard rate = 0.97, 95% CI: 0.79-1.19, P = 0.80; P for interaction = 0.001). CONCLUSIONS: Frail KT recipients are more likely to experience a longer LOS. Longer LOS among nonfrail recipients may be a marker of increased mortality risk. Frailty is a measure of physiologic reserve that may be an important clinical marker of longer surgical LOS.