Pegloticase efficacy and safety in kidney transplant recipients; results of the phase IV, open-label PROTECT clinical trial.

INTRODUCTION: Kidney transplant (KT) recipients have a high prevalence and severity of gout. Pegloticase (pegylated recombinant uricase) rapidly metabolizes serum uric acid (sUA), and its efficacy is not impacted by kidney function. METHODS: This open-label, Phase 4 trial (PROTECT NCT04087720) examined safety and efficacy of pegloticase in 20 participants with KT > 1 year prior to enrollment and with uncontrolled gout (sUA ≥7 mg/dL, intolerance/inefficacy to urate lowering therapy, and ≥1 of the following: tophi, chronic gouty arthritis, ≥2 flares in past year) and functioning KT (estimated glomerular filtration rate [eGFR] ≥15 mL/min/1.73 m2 ) on stable immunosuppression therapy. RESULTS: The primary endpoint was sUA response during month 6 (sUA < 6 mg/dL for ≥80% of time). The study enrolled 20 participants (mean ± SD); age: 53.9 ± 10.9 years, time since KT: 14.7 ± 6.9 years, sUA: 9.4 ± 1.5 mg/dL, gout duration: 8.4 ± 11.6 years; all on ≥2 stable doses of immunosuppression agents. Pegloticase (8 mg intravenous every 2 weeks) in KT recipients with uncontrolled gout showed a high response rate of 89% (16/18 responders). Two participants discontinued treatment solely due to COVID-19 concerns prior to month 6 were not included in the primary analysis. Pegloticase exposures were higher than those historically observed with pegloticase monotherapy, and no anaphylaxis or infusion reaction events occurred during the study. CONCLUSIONS: This improved response rate to pegloticase in the KT population reflects observations from other trials and reports on immunomodulation with pegloticase. As the KT population has a high prevalence of gout and limitations with oral urate lowering medication options, these findings suggest a potential option for uncontrolled gout therapy in KT participants.

SARS-CoV-2 Neutralizing Monoclonal Antibodies for the Treatment of COVID-19 in Kidney Transplant Recipients.

Background: Morbidity and mortality associated with coronavirus disease 2019 (COVID-19) infection in kidney transplant recipients are high and early outpatient interventions to prevent progression to severe disease are needed. SARS-CoV-2 neutralizing mAbs, including bamlanivimab and casirivimab-imdevimab, received emergency use authorization in the United States in November 2020 for treatment of mild to moderate COVID-19 disease. Methods: We performed a retrospective analysis of 27 kidney transplant recipients diagnosed with COVID-19 between July 2020 and February 2021 who were treated with bamlanivimab or casirivimab-imdevimab and immunosuppression reduction. We additionally identified 13 kidney transplant recipients with COVID-19 who had mild to moderate disease at presentation, who did not receive mAbs, and had SARS-CoV-2 serology testing available. Results: There were no deaths or graft failures in either group. Both infusions were well tolerated. Four of the 27 patients treated with mAbs required hospitalization due to COVID-19. Four of 13 patients who did not receive mAbs required hospitalization due to COVID-19. Patients who received mAbs demonstrated measurable anti-SARS-CoV-2 IgG with angiotensin-converting enzyme 2 (ACE2) receptor blocking activity at the highest level detectable at 90 days postinfusion, whereas ACE2 blocking activity acquired from natural immunity in the mAb-untreated group was weak. Conclusions: Bamlanivimab and casirivimab-imdevimab combined with immunosuppression reduction were well tolerated and associated with favorable clinical outcomes in kidney transplant recipients diagnosed with mild to moderate COVID-19.

Trends in Cost Attributable to Kidney Transplantation Evaluation and Waiting List Management in the United States, 2012-2017.

Importance: While recent policy reforms aim to improve access to kidney transplantation for patients with end-stage kidney disease, the cost implications of kidney waiting list expansion are not well understood. The Organ Acquisition Cost Center (OACC) is the mechanism by which Medicare reimburses kidney transplantation programs, at cost, for costs attributable to kidney transplantation evaluation and waiting list management, but these costs have not been well described to date. Objectives: To describe temporal trends in mean OACC costs per kidney transplantation and to identify factors most associated with cost. Design, Setting, and Participants: This economic evaluation included all kidney transplantation waiting list candidates and recipients in the United States from 2012 to 2017. A population-based study of cost center reports was conducted using data from all Center of Medicare & Medicaid-certified transplantation hospitals. Data analysis was conducted from June to August 2021. Exposures: Year, local price index, transplantation and waiting list volume of transplantation program, and comorbidity burden. Main Outcomes and Measures: Mean OACC costs per kidney transplantation. Results: In 1335 hospital-years from 2012 through 2017, Medicare's share of OACC costs increased from $0.95 billion in 2012 to $1.32 billion in 2017 (3.7% of total Medicare End-Stage Renal Disease program expenditure). Median (IQR) OACC costs per transplantation increased from $81 000 ($66 000 to $103 000) in 2012 to $100 000 ($82 000 to $125 000) in 2017. Kidney organ procurement costs contributed to 36% of mean OACC costs per transplantation throughout the study period. During the study period, transplantation hospitals experienced increases in kidney waiting list volume, kidney waiting list active volume, kidney transplantation volume, and comorbidity burden. For a median-sized transplantation program, mean OACC costs per transplantation decreased with more transplants (-$3500 [95% CI, -$4300 to -$2700] per 10 transplants; P < .001) and increased with year ($4400 [95% CI, $3500 to $5300] per year; P < .001), local price index ($1900 [95% CI, $200 to $3700] per 10-point increase; P = .03), patients listed active on the waiting list ($3100 [95% CI, $1700 to $4600] per 100 patients; P < .001), and patients on the waiting list with high comorbidities ($1500 [9% CI, $600 to $2500] per 1% increase in proportion of waitlisted patients with the highest comorbidity score; P = .002). Conclusions and Relevance: In this study, OACC costs increased at 4% per year from 2012 to 2017 and were not solely attributable to the cost of organ procurement. Expanding the waiting list will likely contribute to further increases in the mean OACC costs per transplantation and substantially increase Medicare liability.

Successful Induction of Specific Immunological Tolerance by Combined Kidney and Hematopoietic Stem Cell Transplantation in HLA-Identical Siblings.

Induction of immunological tolerance has been the holy grail of transplantation immunology for decades. The only successful approach to achieve it in patients has been a combined kidney and hematopoietic stem cell transplantation from an HLA-matched or -mismatched living donor. Here, we report the first three patients in Europe included in a clinical trial aiming at the induction of tolerance by mixed lymphohematopoietic chimerism after kidney transplantation. Two female and one male patient were transplanted with a kidney and peripherally mobilized hematopoietic stem cells from their HLA-identical sibling donor. The protocol followed previous studies at Stanford University: kidney transplantation was performed on day 0 including induction with anti-thymocyte globulin followed by conditioning with 10x 1.2 Gy total lymphoid irradiation and the transfusion of CD34+ cells together with a body weight-adjusted dose of donor T cells on day 11. Immunosuppression consisted of cyclosporine A and steroids for 10 days, cyclosporine A and mycophenolate mofetil for 1 month, and then cyclosporine A monotherapy with tapering over 9-20 months. The 3 patients have been off immunosuppression for 4 years, 19 months and 8 months, respectively. No rejection or graft-versus-host disease occurred. Hematological donor chimerism was stable in the first, but slowly declining in the other two patients. A molecular microscope analysis in patient 2 revealed the genetic profile of a normal kidney. No relevant infections were observed, and the quality of life in all three patients is excellent. During the SARS-CoV-2 pandemic, all three patients were vaccinated with the mRNA vaccine BNT162b2 (Comirnaty®), and they showed excellent humoral and in 2 out 3 patients also cellular SARS-CoV-2-specific immunity. Thus, combined kidney and hematopoietic stem cell transplantation is a feasible and successful approach to induce specific immunological tolerance in the setting of HLA-matched sibling living kidney donation while maintaining immune responsiveness to an mRNA vaccine (ClinicalTrials.gov: NCT00365846).

Development of immunosuppressive myeloid cells to induce tolerance in solid organ and hematopoietic cell transplant recipients.

Replacement of failed organs followed by safe withdrawal of immunosuppressive drugs has long been the goal of organ transplantation. We studied changes in the balance of T cells and myeloid cells in the blood of HLA-matched and -mismatched patients given living donor kidney transplants followed by total lymphoid irradiation, anti-thymocyte globulin conditioning, and donor hematopoietic cell transplant to induce mixed chimerism and immune tolerance. The clinical trials were based on a conditioning regimen used to establish mixed chimerism and tolerance in mice. In preclinical murine studies, there was a profound depletion of T cells and an increase in immunosuppressive polymorphonuclear (pmn) myeloid-derived suppressor cells (MDSCs) in the spleen and blood following transplant. Selective depletion of pmn MDSCs in mice abrogated mixed chimerism and tolerance. In our clinical trials, patients given an analogous tolerance conditioning regimen developed similar changes, including profound depletion of T cells and a marked increase in MDSCs in blood posttransplant. Posttransplant pmn MDSCs transiently increased expression of lectin-type oxidized LDL receptor-1, a marker of immunosuppression, and production of the T-cell inhibitor arginase-1. These posttransplant pmn MDSCs suppressed the activation, proliferation, and inflammatory cytokine secretion of autologous T-cell receptor microbead-stimulated pretransplant T cells when cocultured in vitro. In conclusion, we elucidated changes in receptors and function of immunosuppressive myeloid cells in patients enrolled in the tolerance protocol that were nearly identical to those of MDSCs required for tolerance in mice. These trials were registered at www.clinicaltrials.gov as #NCT00319657 and #NCT01165762.

The organ procurement costs of expanding deceased donor organ acceptance criteria: Evidence from a cost function model.

A potential solution to the deceased donor organ shortage is to expand donor acceptability criteria. The procurement cost implications of using nonstandard donors is unknown. Using 5 years of US organ procurement organization (OPO) data, we built a cost function model to make cost projections: the total cost was the dependent variable; production outputs, including the number of donors and organs procured, were the independent variables. In the model, procuring one kidney or procuring both kidneys from double/en bloc transplantation from a single-organ donor resulted in a marginal cost of $55 k (95% confidence interval [CI] $28 k, $99 k) per kidney, and procuring only the liver from a single-organ donor results in a marginal cost of $41 k (95% CI $12 k, $69 k) per liver. Procuring two kidneys for two candidates from a donor lowered the marginal cost to $36 k (95% CI $22 k, $66 k) per kidney, and procuring two kidneys and a liver lowers the marginal cost to $24 k (95% CI $17 k, $45 k) per organ. Economies of scale were observed, where high OPO volume was correlated with lower costs. Despite higher cost per organ than for standard donors, kidney transplantation from nonstandard donors remained cost-effective based on contemporary US data.

Mixed chimerism and acceptance of kidney transplants after immunosuppressive drug withdrawal.

Preclinical studies have shown that persistent mixed chimerism is linked to acceptance of organ allografts without immunosuppressive (IS) drugs. Mixed chimerism refers to continued mixing of donor and recipient hematopoietic cells in recipient tissues after transplantation of donor cells. To determine whether persistent mixed chimerism and tolerance can be established in patients undergoing living donor kidney transplantation, we infused allograft recipients with donor T cells and hematopoietic progenitors after posttransplant lymphoid irradiation. In 24 of 29 fully human leukocyte antigen (HLA)-matched patients who had persistent mixed chimerism for at least 6 months, complete IS drug withdrawal was achieved without subsequent evidence of rejection for at least 2 years. In 10 of 22 HLA haplotype-matched patients with persistent mixed chimerism for at least 12 months, reduction of IS drugs to tacrolimus monotherapy was achieved. Withdrawal of tacrolimus during the second year resulted in loss of detectable chimerism and subsequent rejection episodes, unless tacrolimus therapy was reinstituted. Posttransplant immune reconstitution of naïve B cells and B cell precursors was more rapid than the reconstitution of naïve T cells and thymic T cell precursors. Robust chimerism was observed only among naïve T and B cells but not among memory T cells. No evidence of rejection was observed in all surveillance graft biopsies obtained from mixed chimeric patients withdrawn from IS drugs, and none developed graft-versus-host disease. In conclusion, persistent mixed chimerism established in fully HLA- or haplotype-matched patients allowed for complete or partial IS drug withdrawal without rejection.

A new approach to kidney wait-list management in the kidney allocation system era: Pilot implementation and evaluation.

Kidney transplant wait-list management is becoming increasingly complex. We introduced a novel wait-list management strategy at our center, the Transplant Readiness Assessment Clinic (TRAC), whereby patients whose Kidney Allocation Scores surpass a threshold are actively managed. From January 1, 2016 through June 30, 2017, we evaluated 195 patients through TRAC. Compared to pre-TRAC systems at our institution, TRAC resulted in a higher proportion of activation at 18 months (38% vs 22%-26%, P < 0.0001), despite being enriched in patients with long dialysis duration. TRAC also resulted in a higher proportion of wait-list removal (15% vs 8%-9%, P < 0.05) although combined wait-list removal and death on wait-list did not differ (18% vs 16%-17%). Median time to activation was 356 days from TRAC evaluation. Of the transplant barriers, need for cardiovascular studies was the most common (31%), followed by other medical issues (23%), poor functional status (13%), and psychosocial issues (10%). By concentrating center resources on patients most likely to be transplanted after activation and performing active patient management close to the time of transplant, TRAC has the potential to significantly enhance kidney transplant success in regions with long wait-times.

Macrochimerism and clinical transplant tolerance.

Current theory holds that macrochimerism is essential to the development of transplant tolerance. Hematopoietic cell transplantation from the solid organ donor is necessary to achieve macrochimerism. Over the last 10-20 years, trials of tolerance induction with combined kidney and hematopoietic cell transplantation have moved from the preclinical to the clinical arena. The achievement of macrochimerism in the clinical setting is challenging, and potentially toxic due to the conditioning regimen necessary to hematopoietic cell transplantation and due to the risk of graft-versus-host disease. There are differences in chimerism goals and methods of the three major clinical stage tolerance induction strategies in both HLA-matched and HLA-mismatched living donor kidney transplantation, with consequent differences in efficacy and safety. The Stanford protocol has proven efficacious in the induction of tolerance in HLA-matched kidney transplantation, allowing cessation of immunosuppressive drug therapy in 80% of study participants, with the safety profile of conventional transplantation. In HLA-mismatched transplantation, multi-lineage macrochimerism of over a year's duration can now be consistently achieved with the Stanford protocol, with complete withdrawal of immunosuppressive drug therapy during the second post-transplant year as the next experimental step and test of tolerance.

Developing Consensus-Based Priority Outcome Domains for Trials in Kidney Transplantation: A Multinational Delphi Survey With Patients, Caregivers, and Health Professionals.

BACKGROUND: Inconsistencies in outcome reporting and frequent omission of patient-centered outcomes can diminish the value of trials in treatment decision making. We identified critically important outcome domains in kidney transplantation based on the shared priorities of patients/caregivers and health professionals. METHODS: In a 3-round Delphi survey, patients/caregivers and health professionals rated the importance of outcome domains for trials in kidney transplantation on a 9-point Likert scale and provided comments. During rounds 2 and 3, participants rerated the outcomes after reviewing their own score, the distribution of the respondents' scores, and comments. We calculated the median, mean, and proportion rating 7 to 9 (critically important), and analyzed comments thematically. RESULTS: One thousand eighteen participants (461 [45%] patients/caregivers and 557 [55%] health professionals) from 79 countries completed round 1, and 779 (77%) completed round 3. The top 8 outcomes that met the consensus criteria in round 3 (mean, ≥7.5; median, ≥8; proportion, >85%) in both groups were graft loss, graft function, chronic rejection, acute rejection, mortality, infection, cancer (excluding skin), and cardiovascular disease. Compared with health professionals, patients/caregivers gave higher priority to 6 outcomes (mean difference of 0.5 or more): skin cancer, surgical complications, cognition, blood pressure, depression, and ability to work. We identified 5 themes: capacity to control and inevitability, personal relevance, debilitating repercussions, gaining awareness of risks, and addressing knowledge gaps. CONCLUSIONS: Graft complications and severe comorbidities were critically important for both stakeholder groups. These stakeholder-prioritized outcomes will inform the core outcome set to improve the consistency and relevance of trials in kidney transplantation.

HCV infection is associated with lower survival in simultaneous liver kidney transplant recipients in the United States.

BACKGROUND: The frequency of simultaneous liver kidney transplantation (SLKT) has been increasing over the past decade. Hepatitis C virus (HCV) infection is the most common indication for liver transplantation in the United States. Given the rising prevalence of HCV-related SLKT, it is important to understand the impact of HCV in this patient population. METHODS: We conducted a retrospective cohort study using data from the United Network for Organ Sharing registry to assess adult patients undergoing SLKT in the United States from 2003 to 2012. Patient survival following SLKT was assessed using Kaplan-Meier methods and multivariate Cox proportional hazards models. RESULTS: Patients infected with non-HCV have significantly lower survival following SLKT compared to non-HCV patients at three (three-yr survival: 71.0% vs. 78.9%, p < 0.01) and five yr (five-yr survival: 61.4% vs. 72.5%, p < 0.01). The results of multivariate regression analyses demonstrated that patients infected with HCV had significantly lower survival following SLKT than patients with non-HCV disease (HR 1.41, 95% CI, 1.19-1.67, p < 0.001). In addition, lower post-SLKT survival was noted among patients with diabetes (HR 1.34, 95% CI, 1.13-1.58, p < 0.001) and hepatocellular carcinoma (HR 1.60, 95% CI, 1.17-2.18, p < 0.01). CONCLUSIONS: Hepatitis C infection is associated with lower patient survival following SLKT.

Correlates and outcomes of warfarin initiation in kidney transplant recipients newly diagnosed with atrial fibrillation.

In the kidney transplant population with atrial fibrillation (AF), evidence regarding the effectiveness and safety of warfarin treatment is lacking. We used fee-for-service Medicare claims to identify kidney transplant recipients with newly diagnosed AF from the United States Renal Data System. Warfarin use within 30 days of AF diagnosis was ascertained from Medicare Part D prescription claims (2007-11) or using a validated algorithm (1997-2011). The study end points were (i) the composite of death, stroke or gastrointestinal bleed, (ii) death and (iii) death-censored graft failure. Warfarin user and non-user groups were balanced using inverse probability of treatment weighting and hazard ratios were (HRs) estimated using Cox regression. Among 718 subjects with an indication for anticoagulation, 24% initiated warfarin treatment within 30 days of AF diagnosis. Age was the only independent correlate of warfarin use [odds ratio = 1.02 per year; 95% confidence interval (95% CI) 1.01-1.04]. In the larger cohort of 6492 patients with AF, warfarin use [(23.5%) versus non-use (76.5%)] was associated with small and non-significant reductions in the composite of death, stroke or gastrointestinal bleed (HR = 0.92; 95% CI 0.83-1.02), death (HR = 0.92; 95% CI 0.82-1.02) and death-censored graft failure (HR = 0.90; 95% CI 0.76-1.08). Our study suggests the need for clinical trials of warfarin use in the kidney transplant population with AF.

Living donor evaluation and exclusion: the Stanford experience.

BACKGROUND: The proportion of prospective living donors disqualified for medical reasons is unknown. The objective of this study is to delineate and quantify specific reasons for exclusion of prospective living donors from kidney donation. METHODS: All adult prospective kidney donors who contacted our transplant program between October 1, 2007 and April 1, 2009 were included in our analysis (n = 484). Data were collected by review of an electronic transplant database. RESULTS: Of the 484 prospective donors, 39 (8%) successfully donated, 229 (47%) were excluded, 104 (22%) were actively undergoing evaluation, and 112 (23%) were withdrawn before evaluation was complete. Criteria for exclusion were medical (n = 150), psychosocial (n = 22), or histocompatibility (n = 57) reasons. Of the 150 prospective donors excluded for medical reasons, 79% were excluded because of obesity, hypertension, nephrolithiasis, and/or abnormal glucose tolerance. One hundred and forty-seven (61%) intended recipients had only one prospective living donor, of whom 63 (42%) were excluded. CONCLUSIONS: A significant proportion of prospective living kidney donors were excluded for medical reasons such as obesity (body mass index >30), hypertension, nephrolithiasis, and abnormal glucose tolerance. Longer-term studies are needed to characterize the risks to medically complex kidney donors and the potential risks and benefits afforded to recipients.

Tolerance and chimerism after renal and hematopoietic-cell transplantation.

We describe a recipient of combined kidney and hematopoietic-cell transplants from an HLA-matched donor. A post-transplantation conditioning regimen of total lymphoid irradiation and antithymocyte globulin allowed engraftment of the donor's hematopoietic cells. The patient had persistent mixed chimerism, and the function of the kidney allograft has been normal for more than 28 months since discontinuation of all immunosuppressive drugs. Adverse events requiring hospitalization were limited to a 2-day episode of fever with neutropenia. The patient has had neither rejection episodes nor clinical manifestations of graft-versus-host disease.