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Ram Jagannathan,1 Kanya Rajagopalan,2 Julien Hogan,3,4 Allyson Hart,5,6 Kenneth A Newell,4 Stephen O Pastan,7 Rachel E Patzer4,7,8 1Department of Medicine, Division of Hospital Medicine, Emory University School of Medicine, Atlanta, GA, USA; 2Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, GA, USA; 3Pediatric Nephrology Department, Robert Debre University Hospital, Paris, 75019, France; 4Department of Surgery, Division of Transplantation, Emory University School of Medicine, Atlanta, GA, USA; 5Division of Nephrology, Department of Medicine, Hennepin Healthcare, Minneapolis, MN, USA; 6University of Minnesota Medical School, Minneapolis, MN, USA; 7Department of Medicine, Emory University School of Medicine, Atlanta, GA, USA; 8Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USACorrespondence: Ram JagannathanDepartment of Medicine, Division of Hospital Medicine, Emory University School of Medicine, Atlanta, GA, 30322, USAEmail ram.jagannathan@emory.eduBackground: Two coding risk variants in the Apo L1 gene (APOL1) underlie most of the excess risk for kidney diseases in recent African ancestry patients. Strength and consistency of the relationship between APOL1 high-risk genotypes and the risk of chronic kidney diseases (CKD) and end-stage renal disease (ESRD) are not uniform.Objective: To conduct a systematic review and meta-analysis of prospective studies assessing the association of APOL1 genotypes and the risk of developing CKD, ESRD, and CKD to ESRD in adults.Methods: Systematic search of MEDLINE, EMBASE, and Google Scholar was performed for prospective studies assessing the associations between APOL1 genotypes and CKD, ESRD, and progression from CKD to ESRD. Secondary analyses were to evaluate the annual kidney function change by APOL1 gene status. Random effects models were used to estimate pooled risk ratios (RRs) and weighted mean differences for outcomes of interest.Results: The search yield 10 prospective during a follow-up period ranging from 4.4 to 25 years. The high-risk APOL1 genotype was associated with the incidence of CKD (RR:1.41[95% CI: 1.14– 1.75]), the progression from CKD to ESRD (RR: 1.70[95% CI:1.44; 2.01]) compared with the low-risk APOL1 genotype. There was no appreciable association between high-risk APOL1 genotype with the incidence of ESRD. Furthermore, high-risk APOL1 genotype was associated with a marginal decrement in the annual eGFR decline (− 0.55[95% CI: − 0.94 to − 0.16]) mL/min/1.73m2 compared with low-risk APOL1 genotype status.Conclusion: In summary, African Americans carrying APOL1 high-risk genotypes are at increased risk of developing CKD and ESRD. Given that the APOL1 risk alleles are common among individuals with African ancestry, with ∼ 18% of African Americans carrying high-risk alleles, these findings highlight the potential identification of subgroups of patients who may benefit from APOL1 screening and developing culturally-appropriate interventions.Keywords: APOL1, chronic kidney disease, end-stage renal diseases, disparities, African Americans

Vaccinating patients receiving dialysis may prevent morbidity and mortality in this vulnerable population. The National Forum of End-Stage Renal Disease Networks (the Forum) published a revised vaccination toolkit in 2021 to update evidence and recommendations on vaccination for patients receiving dialysis. Significant changes in the last 10 years include more data supporting the use of a high-dose influenza vaccine, the introduction of the Heplisav-B vaccine for hepatitis B, and changes in pneumococcal vaccines, including the approval of the PCV15 and PCV20 to replace the PCV13 and PPSV23 vaccines. Additional key items include the introduction of vaccines against severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19), and a new vaccine to prevent respiratory syncytial virus disease. Historically, influenza and pneumococcal vaccinations were routinely administered by dialysis facilities, and because of possible risks of hematogenous spread of hepatitis B, dialysis providers often have detailed hepatitis B vaccine protocols. In March 2021, COVID-19 vaccines were made available for dialysis facilities to administer, although with the end of the public health emergency, vaccine policies by dialysis facilities against COVID-19 remains uncertain. The respiratory syncytial virus vaccine was authorized in 2023, and how dialysis facilities will approach this vaccine also remains uncertain. This review summarizes the Forums vaccination toolkit and discusses the role of the dialysis facility in vaccinating patients to reduce the risk of severe infections.

INTRODUCTION: The Allocation System for changes in Equity in Kidney Transplantation (ASCENT) study was a hybrid type 1 trial of a multicomponent intervention among 655 US dialysis facilities with low kidney transplant waitlisting to educate staff and patients about kidney allocation system (KAS) changes and increase access to and reduce racial disparities in waitlisting. Intervention components included a staff webinar, patient and staff educational videos, and facility-specific feedback reports. METHODS: Implementation outcomes were assessed using the Reach, Effectiveness, Adoption, Implementation, and Maintenance Framework. Postimplementation surveys were administered among intervention group facilities (n = 334); interviews were conducted with facility staff (n = 6). High implementation was defined as using 3 to 4 intervention components, low implementation as using 1 to 2 components, and nonimplementation as using no components. RESULTS: A total of 331 (99%) facilities completed the survey; 57% were high implementers, 31% were low implementers, and 12% were nonimplementers. Waitlisting events were higher or similar among high versus low implementer facilities for incident and prevalent populations; for Black incident patients, the mean proportion waitlisted in low implementer facilities was 0.80% (95% confidence interval [CI]: 0.73-0.87) at baseline and 0.55% at 1-year (95% CI: 0.48-0.62) versus 0.83% (95% CI: 0.78-0.88) at baseline and 1.40% at 1-year (95% CI: 1.35-1.45) in high implementer facilities. Interviews revealed that the intervention helped facilities prioritize transplant education, but that intervention components were not uniformly shared. CONCLUSION: The findings provide important context to interpret ASCENT effectiveness results and identified key barriers and facilitators to consider for future modification and scale-up of multilevel, multicomponent interventions in dialysis settings.

Bacterial flagella and type IV pili (TFP) are surface appendages that enable motility and mechanosensing through distinct mechanisms. These structures were previously thought to have no components in common. Here, we report that TFP and some flagella share proteins PilO, PilN, and PilM, which we identified as part of the Helicobacter pylori flagellar motor. H. pylori mutants lacking PilO or PilN migrated better than wild type in semisolid agar because they continued swimming rather than aggregated into microcolonies, mimicking the TFP-regulated surface response. Like their TFP homologs, flagellar PilO/PilN heterodimers formed a peripheral cage that encircled the flagellar motor. These results indicate that PilO and PilN act similarly in flagella and TFP by differentially regulating motility and microcolony formation when bacteria encounter surfaces.

OBJECTIVE: For the majority of patients with lupus nephritis-related end-stage kidney disease (LN-ESKD), kidney transplant is associated with better outcomes than dialysis. Access to kidney transplant requires an initial referral to a transplant center and medical evaluation prior to waitlisting. The studys objective was to examine access to these early steps in the kidney transplant process among patients with LN-ESKD. METHODS: Adults who began treatment for ESKD in the Southeast, Northeast, New York, or Ohio River Valley U.S. regions from 1/1/2012 to 12/31/2019, followed through 6/30/2021, were identified from the United States Renal Data System. Referral and evaluation start data were collected from 28 of 48 transplant centers across these regions. The exposure was primary cause of ESKD (LN-ESKD vs other-ESKD). The outcomes were referral and evaluation start at a transplant center. Cox models quantified the association between LN-ESKD (vs other-ESKD) and referral and evaluation start. RESULTS: Among 192,318 patients initiating treatment for ESKD, 0.4% had LN-ESKD. Over half (58%) of LN-ESKD patients were referred before study end, and among those referred, 66% started the evaluation. In adjusted analyses, patients with LN-ESKD were referred (HR: 1.09, 95% CI: 0.99, 1.19) and started the transplant evaluation (HR: 1.13, 95% CI: 1.00, 1.28) at a higher rate than patients with other-ESKD. Among referred patients with LN-ESKD, the median time from ESKD start to referral was 2.9 months (IQR:

Abstract Background Determining whether a patient is eligible for kidney transplantation is complex. In this study, we estimate what proportion of patients with end-stage kidney disease (ESKD) might have been suitable candidates for kidney transplantation but were not referred. Methods We identified 43,952 people initiating dialysis for kidney failure between 2012 and 2017 in the states of Georgia, North Carolina, or South Carolina from the United States Renal Data System and linked to the Early-Steps to Transplant Access Registry to obtain data on referral and waitlisting up until December 2020. We identified ‘good transplant candidates’ as those who were waitlisted within 2-years of referral, among all patients referred within 1-year of dialysis initiation. Using propensity score cut-offs, logistic regression, and area under the curve (AUC), we then estimated the proportion of individuals who may have been good transplant candidates, but were not referred. Results Overall, 42.6% of incident dialysis patients were referred within one year and among them, 32.9% were waitlisted within 2 years of referral. Our model had reasonably good discrimination for identifying good transplant candidates with an AUC of 0.70 (95%CI 0.69–0.71), sensitivity of 0.68 and specificity of 0.61. Overall, 25% of individuals not referred for transplant may have been ‘good’ transplant candidates. Adding these patients to the existing 18,725 referred patients would increase the proportion of incident ESKD patients being referred within one year from 42.6% to 57.2% (a ~ 14.6% increase). Conclusions In this study, we show that a significant proportion of potentially good transplant candidates are not being referred for transplant. A ~ 14% increase in the proportion of patients being referred from dialysis facilities is both a meaningful and realistic goal and could lead to more qualified patients being referred and subsequently waitlisted for a lifesaving transplant.

BackgroundLMB-100 is a mesothelin (MSLN)-targeting recombinant immunotoxin (iTox) carrying a Pseudomonas exotoxin A payload that has shown promise against solid tumors, however, efficacy is limited by the development of neutralizing anti-drug antibodies (ADAs). Tofacitinib is an oral Janus Kinase (JAK) inhibitor that prevented ADA formation against iTox in preclinical studies.MethodsA phase 1 trial testing LMB-100 and tofacitinib in patients with MSLN-expressing cancers (pancreatic adenocarcinoma, n=13; cholangiocarcinoma, n=1; appendiceal carcinoma, n=1; cystadenocarcinoma, n=1) was performed to assess safety and to determine if tofacitinib impacted ADA formation. Participants were treated for up to 3 cycles with LMB-100 as a 30-minute infusion on days 4, 6, and 8 at two dose levels (100 and 140 µg/kg) while oral tofacitinib was administered for the first 10 days of the cycle (10 mg BID). Peripheral blood was collected for analysis of ADA levels, serum cytokines and circulating immune subsets.ResultsThe study was closed early due to occurrence of drug-induced pericarditis in 2 patients. Pericarditis with the combination was not reproducible in a transgenic murine model containing human MSLN. Two of 4 patients receiving all 3 cycles of treatment maintained effective LMB-100 levels, an unusual occurrence. Sustained increases in systemic IL-10 and TNF-α were seen, a phenomenon not observed in prior LMB-100 studies. A decrease in activated T cell subsets and an increase in circulating immunosuppressive myeloid populations occurred. No radiologic decreases in tumor volume were observed.DiscussionFurther testing of tofacitinib to prevent ADA formation is recommended in applicable non-malignant disease settings.Clinical trial registrationhttps://www.clinicaltrials.gov/study/NCT04034238.

Introduction: We examined sex/gender disparities across the continuum of transplant care by attributed cause of end-stage kidney disease (ESKD). Methods: All adults (18–79 years; N = 43,548) with new-onset ESKD in Georgia, North Carolina, or South Carolina between 2015 and 2019 were identified from the United States Renal Data System (USRDS). Individuals were linked to the Early Steps to Transplant Access Registry (E-STAR) to obtain data on referral and evaluation. Waitlisting data was ascertained from USRDS. Using a Cox-proportional hazards model, with follow-up through 2020, we assessed the association between sex/gender and referral within 12 months (among all incident dialysis patients), evaluation start within 6 months (among referred patients), and waitlisting (among all evaluated patients) by attributed cause of ESKD (type 1 diabetes mellitus, type 2 diabetes mellitus, hypertension, glomerulonephritis, cystic disease, and other). Results: Overall, women (vs. men) with type 2 diabetes-attributed ESKD were 13% (crude hazard ratio [HR]: 0.87 [0.83–0.91]), 14% (crude HR: 0.86 [0.81–0.91]), and 14% (crude HR: 0.86 [0.78–0.94]) less likely to be referred, evaluated, and waitlisted, respectively. Women (vs. men) with hypertension-attributed ESKD were 14% (crude HR: 0.86 [0.82–0.90]) and 8% (crude HR: 0.92 [0.87–0.98]) less likely to be referred and evaluated, respectively, but similarly likely to be waitlisted once evaluated (crude HR: 1.06 [0.97–1.15]). For all other attributed causes of ESKD, there was no sex/gender disparity in referral, evaluation, or waitlisting rates. Conclusion: In the Southeast United States, sex/gender disparities in early access to kidney transplantation are specific to people with ESKD attributed to type 2 diabetes and hypertension.

Vaccinating patients receiving dialysis may prevent morbidity and mortality in this vulnerable population. The National Forum of End-Stage Renal Disease Networks (the Forum) published a revised vaccination toolkit in 2021 to update evidence and recommendations on vaccination for patients receiving dialysis. Significant changes in the last 10 years include more data supporting the use of a high-dose influenza vaccine, the introduction of the Heplisav-B vaccine for hepatitis B, and changes in pneumococcal vaccines, including the approval of the PCV15 and PCV20 to replace the PCV13 and PPSV23 vaccines. Additional key items include the introduction of vaccines against severe acute respiratory syndrome coronavirus 2, the virus that causes coronavirus disease 2019 (COVID-19), and a new vaccine to prevent respiratory syncytial virus disease. Historically, influenza and pneumococcal vaccinations were routinely administered by dialysis facilities, and because of possible risks of hematogenous spread of hepatitis B, dialysis providers often have detailed hepatitis B vaccine protocols. In March 2021, COVID-19 vaccines were made available for dialysis facilities to administer, although with the end of the public health emergency, vaccine policies by dialysis facilities against COVID-19 remains uncertain. The respiratory syncytial virus vaccine was authorized in 2023, and how dialysis facilities will approach this vaccine also remains uncertain. This review summarizes the Forum’s vaccination toolkit and discusses the role of the dialysis facility in vaccinating patients to reduce the risk of severe infections.

We investigated the role of mesothelin (Msln) and thymocyte differentiation antigen 1 (Thy1) in the activation of fibroblasts across multiple organs and demonstrated that Msln-/- mice are protected from cholestatic fibrosis caused by Mdr2 (multidrug resistance gene 2) deficiency, bleomycin-induced lung fibrosis, and UUO (unilateral urinary obstruction)-induced kidney fibrosis. On the contrary, Thy1-/- mice are more susceptible to fibrosis, suggesting that a Msln-Thy1 signaling complex is critical for tissue fibroblast activation. A similar mechanism was observed in human activated portal fibroblasts (aPFs). Targeting of human MSLN+ aPFs with two anti-MSLN immunotoxins killed fibroblasts engineered to express human mesothelin and reduced collagen deposition in livers of bile duct ligation (BDL)-injured mice. We provide evidence that antimesothelin-based therapy may be a strategy for treatment of parenchymal organ fibrosis.

Rationale & Objective: Patients with kidney failure from racial and ethnic minority groups and older patients have reduced access to the transplant waitlist relative to White and younger patients. Although racial disparities in the waitlisting group have declined after the 2014 kidney allocation system change, whether there is intersectionality of race and age in waitlisting access is unknown. Study Design: Retrospective cohort study. Setting & Participants: 439,455 non-Hispanic White and non-Hispanic Black US adults initiating dialysis between 2015 and 2019 were identified from the United States Renal Data System, and followed through 2020. Exposures: Patient race and ethnicity (non-Hispanic White and non-Hispanic Black) and age group (18-29, 30-49, 50-64, and 65-80 years). Outcomes: Placement on the United Network for Organ Sharing deceased donor waitlist. Analytical Approach: Age- and race-stratified waitlisting rates were compared. Multivariable Cox proportional hazards models, censored for death, examined the association between race and waitlisting, and included interaction term for race and age. Results: Over a median follow-up period of 1 year, the proportion of non-Hispanic White and non-Hispanic Black patients waitlisted was 20.7% and 20.5%, respectively. In multivariable models, non-Hispanic Black patients were 14% less likely to be waitlisted (aHR, 0.86, 95% CI, 0.77-0.95). Relative differences between non-Hispanic Black and non-Hispanic White patients were different by age group. Non-Hispanic Black patients were 27%, 12%, and 20% less likely to be waitlisted than non-Hispanic White patients for ages 18-29 years (aHR, 0.73; 95% CI, 0.61-0.86), 50-64 (aHR, 0.88; 95% CI, 0.80-0.98), and 65-80 years (aHR, 0.80; 95% CI, 0.71-0.90), respectively, but differences were attenuated among patients aged 30-49 years (aHR, 0.89; 95% CI, 0.77-1.02). Limitations: Race and ethnicity data is physician reported, residual confounding, and analysis is limited to non-Hispanic White and non-Hispanic Black patients. Conclusions: Racial disparities in waitlisting exist between non-Hispanic Black and non-Hispanic White individuals and are most pronounced among younger patients with kidney failure. Results suggest that interventions to address inequalities in waitlisting may need to be targeted to younger patients with kidney failure. Plain-Language Summary: Research has shown that patients from racial and ethnic minority groups and older patients have reduced access to transplant waitlisting relative to White and younger patients; nevertheless, how age impacts racial disparities in waitlisting is unknown. We compared waitlisting between non-Hispanic Black and non-Hispanic White patients with incident kidney failure, within age strata, using registry data for 439,455 US adults starting dialysis (18-80 years) during 2015-2019. Overall, non-Hispanic Black patients were less likely to be waitlisted and relative differences between the two racial groups differed by age. After adjusting for patient-level factors, the largest disparity in waitlisting was observed among adults aged 18-29 years. These results suggest that interventions should target younger adults to reduce disparities in access to kidney transplant waitlisting.

Abstract LMB‐100 is a novel immune‐conjugate (immunotoxin) that targets mesothelin. A phase 1/2 clinical trial was conducted (NCT02810418) with primary objectives assessing the safety and efficacy of LMB‐100 ± nab‐paclitaxel. Participant blood samples were analyzed for changes in serum cytokines and circulating immune cell subsets associated with response or toxicity. On Arm A, participants (n = 20) received standard 30‐minute LMB‐100 infusion with nab‐paclitaxel. Although clinical efficacy was observed, the combination caused intolerable capillary leak syndrome (CLS), a major toxicity of unclear etiology that affects many immunotoxin drugs. Participants developing CLS experienced rapid elevations in IFNγ and IL‐8 compared to those without significant CLS, along with midcycle increases in Ki‐67‐ CD4 T cells that were CD38, HLA‐DR, or TIM3 positive. Additionally, a strong increase in activated CD4 and CD8 T cells and a concurrent decrease in Tregs were seen in the single Arm A patient achieving a partial response. In Arm B, administration of single agent LMB‐100 to participants (n = 20) as a long infusion given over 24–48 h was investigated based on pre‐clinical data that this format could reduce CLS. An optimal dose and schedule of long infusion LMB‐100 were identified, but no clinical efficacy was observed even in patients receiving LMB‐100 in combination with nab‐paclitaxel. Despite this, both Arm A and B participants experienced increases in specific subsets of proliferating CD4 and CD8 T cells following Cycle 1 treatment. In summary, LMB‐100 treatment causes systemic immune activation. Inflammatory and immune changes that accompany drug associated CLS were characterized for the first time.

INTRODUCTION: The Allocation System Changes for Equity in Kidney Transplantation (ASCENT) trial was a cluster-randomized pragmatic, effectiveness-implementation study designed to test whether a multicomponent educational intervention targeting leadership, clinic staff, and patients in dialysis facilities improved knowledge and awareness of the 2014 Kidney Allocation System (KAS) change. METHODS: Participants included 690 dialysis facility medical directors, nephrologists, social workers, and other staff within 655 US dialysis facilities, with 51% (n = 334) in the intervention group and 49% (n = 321) in the control group. Intervention activities included a webinar targeting medical directors and facility staff, an approximately 10-minute educational video targeting dialysis staff, an approximately 10-minute educational video targeting patients, and a facility-specific audit and feedback report of transplant performance. The control group received a standard United Network for Organ Sharing brochure. Provider knowledge was a secondary outcome of the ASCENT trial and the primary outcome of this study; knowledge was assessed as a cumulative score on a 5-point Likert scale (higher score = greater knowledge). Intention-to-treat analysis was used. RESULTS: At baseline, nonintervention providers had a higher mean knowledge score (mean ± SD, 2.45 ± 1.43) than intervention providers (mean ± SD, 2.31 ± 1.46). After 3 months, the average knowledge score was slightly higher in the intervention (mean ± SD, 3.14 ± 1.28) versus nonintervention providers (mean ± SD, 3.07 ± 1.24), and the estimated mean difference in knowledge scores between the groups at follow-up minus the mean difference at baseline was 0.25 (95% confidence interval [CI], 0.11-0.48; P = 0.039). The effect size (0.41) was low to moderate. CONCLUSION: Dialysis facility provider education could help extend the impact of a national policy change in organ allocation.

Variability in transplant access exists, but barriers to referral and evaluation are underexplored due to lack of national surveillance data. We examined referral for kidney transplantation evaluation and start of the evaluation among 34 857 incident, adult (18-79 years) end-stage kidney disease patients from 690 dialysis facilities in the United States Renal Data System from January 1, 2012 through August 31, 2016, followed through February 2018 and linked data to referral and evaluation data from nine transplant centers in Georgia, North Carolina, and South Carolina. Multivariable-adjusted competing risk analysis examined each outcome. The median within-facility cumulative percentage of patients referred for kidney transplantation within 1 year of dialysis at the 690 dialysis facilities in Network 6 was 33.7% (interquartile range [IQR]: 25.3%-43.1%). Only 48.3% of referred patients started the transplant evaluation within 6 months of referral. In multivariable analyses, factors associated with referral vs evaluation start among those referred at any time differed. For example, black, non-Hispanic patients had a higher rate of referral (hazard ratio [HR]: 1.22; 95% confidence interval [CI]: 1.18-1.27), but lower evaluation start among those referred (HR: 0.93; 95% CI: 0.88-0.98), vs white non-Hispanic patients. Barriers to transplant varied by step, and national surveillance data should be collected on early transplant steps to improve transplant access.

IntroductionMuch of the higher risk for end-stage kidney disease (ESKD) in African American individuals relates to ancestry-specific variation in the apolipoprotein L1 gene (APOL1). Relative to kidneys from European American deceased-donors, kidneys from African American deceased-donors have shorter allograft survival and African American living-kidney donors more often develop ESKD. The National Institutes of Health (NIH)-sponsored APOL1 Long-term Kidney Transplantation Outcomes Network (APOLLO) is prospectively assessing kidney allograft survival from donors with recent African ancestry based on donor and recipient APOL1 genotypes.MethodsAPOLLO will evaluate outcomes from 2614 deceased kidney donor-recipient pairs, as well as additional living-kidney donor-recipient pairs and unpaired deceased-donor kidneys.ResultsThe United Network for Organ Sharing (UNOS), Association of Organ Procurement Organizations, American Society of Transplantation, American Society for Histocompatibility and Immunogenetics, and nearly all U.S. kidney transplant programs, organ procurement organizations (OPOs), and histocompatibility laboratories are participating in this observational study. APOLLO employs a central institutional review board (cIRB) and maintains voluntary partnerships with OPOs and histocompatibility laboratories. A Community Advisory Council composed of African American individuals with a personal or family history of kidney disease has advised the NIH Project Office and Steering Committee since inception. UNOS is providing data for outcome analyses.ConclusionThis article describes unique aspects of the protocol, design, and performance of APOLLO. Results will guide use of APOL1 genotypic data to improve the assessment of quality in deceased-donor kidneys and could increase numbers of transplanted kidneys, reduce rates of discard, and improve the safety of living-kidney donation.

Although research shows that minorities exhibit higher levels of medical mistrust, perceived racism, and discrimination in healthcare settings, the degree to which these underlying sociocultural factors preclude end-stage renal disease (ESRD) patients from initiating kidney transplant evaluation is unknown. We telephone surveyed 528 adult ESRD patients of black or white race referred for evaluation to a Georgia transplant center (N = 3) in 2014-2016. We used multivariable logistic regression to examine associations between sociocultural factors and evaluation initiation, adjusting for demographic, clinical, and socioeconomic characteristics. Despite blacks (n = 407) reporting higher levels of medical mistrust (40.0% vs 26.4%, P

Abstract Podoplanin (PDPN) is intensely expressed on the podocyte membrane in an evolutionally conserved manner. CLEC-2, the endogenous ligand of PDPN, is highly expressed in platelets and also exists in a soluble form in plasma. Normally, podocytes are sequestered from CLEC-2, but when the glomerular barrier is injured, podocytes gain access to CLEC-2. We tested the effects of CLEC-2 in podocytes in vitro and in vivo. Cultured podocytes treated with Fc-CLEC-2 demonstrated that CLEC-2 induced the dephosphorylation of ezrin, radixin, and moesin (ERM) proteins. Podocytes treated with Fc-CLEC-2 also showed the dissociation of F-actin filaments from PDPN, F-actin degradation, detachment, and round morphology. Next, we perfused normal mouse kidney in vivo with FLAG-CLEC-2. CLEC-2 induced dephosphorylation of ERM and widening of the foot processes of podocytes. Platelets were detected by immunostaining for CD41 in the urine of mice with podocyte injury, indicating that podocytes can encounter platelets when glomeruli are injured. Collectively, these observations suggest that when platelets leak through the injured glomeruli, CLEC-2 from the platelets acts on PDPN in podocytes and induces morphological change and detachment, which may further aggravate podocyte injury. Thus, PDPN on podocytes may work as a leaked-platelet sensor.

New treatments are required to enhance current therapies for lung cancer. Mesothelin is a surface protein overexpressed in non-small cell lung cancer (NSCLC) that shows promise as an immunotherapeutic target in phase I clinical trials. However, the immunosuppressive environment in NSCLC may limit efficacy of these therapies. We applied time-of-flight mass cytometry to examine the state of circulating mononuclear cells in fourteen patients undergoing treatment for unresectable lung cancer. Six patients had earlier stage NSCLC (I-IVA) and eight had highly advanced NSCLC (IVB). The advanced NSCLC patients relapsed with greater frequency than the earlier stage patients. Before treatment, patients with very advanced NSCLC had a greater proportion of CD14- myeloid cells than patients with earlier NSCLC. These patients also had fewer circulating natural killer (NK) cells bearing an Fc receptor, CD16, which is crucial to antibody-dependent cellular cytotoxicity. We designed a high affinity tri-specific killer engager (TriKE®) to enhance NK cytotoxicity against mesothelin+ targets in this environment. The TriKE consisted of CD16 and mesothelin binding elements linked together by IL-15. TriKE enhanced proliferation of lung cancer patient NK cells in vitro. Lung cancer lines are refractory to NK cell killing, but the TriKE enhanced cytotoxicity and cytokine production by patient NK cells when challenged with tumor. Importantly, TriKE triggered NK cell responses from patients at all stages of disease and treatment, suggesting TriKE can enhance current therapies. These pre-clinical studies suggest mesothelin-targeted TriKE has the potential to overcome the immunosuppressive environment of NSCLC to treat disease.

This is a pivotal, multicenter, open-label study of moxetumomab pasudotox, a recombinant CD22-targeting immunotoxin, in hairy cell leukemia (HCL), a rare B cell malignancy with high CD22 expression. The study enrolled patients with relapsed/refractory HCL who had ≥2 prior systemic therapies, including ≥1 purine nucleoside analog. Patients received moxetumomab pasudotox 40 µg/kg intravenously on days 1, 3, and 5 every 28 days for ≤6 cycles. Blinded independent central review determined disease response and minimal residual disease (MRD) status. Among 80 patients (79% males; median age, 60.0 years), durable complete response (CR) rate was 30%, CR rate was 41%, and objective response rate (CR and partial response) was 75%; 64 patients (80%) achieved hematologic remission. Among complete responders, 27 (85%) achieved MRD negativity by immunohistochemistry. The most frequent adverse events (AEs) were peripheral edema (39%), nausea (35%), fatigue (34%), and headache (33%). Treatment-related serious AEs of hemolytic uremic syndrome (7.5%) and capillary leak syndrome (5%) were reversible and generally manageable with supportive care and treatment discontinuation (6 patients; 7.5%). Moxetumomab pasudotox treatment achieved a high rate of independently assessed durable response and MRD eradication in heavily pretreated patients with HCL, with acceptable tolerability.

The impact of a new national kidney allocation system (KAS) on access to the national deceased-donor waiting list (waitlisting) and racial/ethnic disparities in waitlisting among US end-stage renal disease (ESRD) patients is unknown. We examined waitlisting pre- and post-KAS among incident (N = 1 253 100) and prevalent (N = 1 556 954) ESRD patients from the United States Renal Data System database (2005-2015) using multivariable time-dependent Cox and interrupted time-series models. The adjusted waitlisting rate among incident patients was 9% lower post-KAS (hazard ratio [HR]: 0.91; 95% confidence interval [CI], 0.90-0.93), although preemptive waitlisting increased from 30.2% to 35.1% (P

BACKGROUND: The Reducing Disparities in Access to kidNey Transplantation Community Study (RaDIANT) was an End-Stage Renal Disease (ESRD) Network 6-developed, dialysis facility-level randomized trial testing the effectiveness of a 1-year multicomponent education and quality improvement intervention in increasing referral for kidney transplant evaluation among selected Georgia dialysis facilities. METHODS: To assess implementation of the RaDIANT intervention, we conducted a process evaluation at the conclusion of the intervention period (January-December 2014). We administered a 20-item survey to the staff involved with transplant education in 67 dialysis facilities randomized to participate in intervention activities. Survey items assessed facility participation in the intervention (fidelity and reach), helpfulness and willingness to continue intervention activities (sustainability), suggestions for improving intervention components (sustainability), and factors that may have influenced participation and study outcomes (context). We defined high fidelity to the intervention as completing 11 or more activities, and high participation in an activity as having at least 75% participation across intervention facilities. RESULTS: Staff from 65 of the 67 dialysis facilities completed the questionnaire, and more than half (50.8%) reported high adherence (fidelity) to RaDIANT intervention requirements. Nearly two-thirds (63.1%) of facilities reported that RaDIANT intervention activities were helpful or very helpful, with 90.8% of facilities willing to continue at least one intervention component beyond the study period. Intervention components with high participation emphasized staff and patient-level education, including in-service staff orientations, patient and family education programs, and patient educational materials. Suggested improvements for intervention activities emphasized addressing financial barriers to transplantation, with financial education materials perceived as most helpful among RaDIANT educational materials. Variation in facility-level fidelity of the RADIANT intervention did not significantly influence the mean difference in proportion of patients referred pre- (2013) and post-intervention (2014). CONCLUSIONS: We found high fidelity to the RaDIANT multicomponent intervention at the majority of intervention facilities, with sustainability of select intervention components at intervention facilities and feasibility for dissemination across ESRD Networks. Future modification of the intervention should emphasize financial education regarding kidney transplantation and amend intervention components that facilities perceive as time-intensive or non-sustainable. TRIAL REGISTRATION: Clinicaltrials.gov number NCT02092727 . Registered 13 Mar 2014 (retrospectively registered).

It is unknown whether dialysis facility staff are aware of the new kidney allocation system implemented in December 2014, which changed how deceased donor kidneys are allocated and waiting time is calculated. U.S. dialysis facilities with low annual waitlisting (

Introduction With its proven effectiveness, indoor residual spraying (IRS) as a malaria vector control strategy forms one of the reliable vector control strategies, especially when at least 80% of the population is covered. However, to date, there is uncertainty regarding the consequences of IRS withdrawal on malaria control when there is no clear exit strategy in place. Therefore, there is a need to comprehensively update literature regarding malaria burden indicators when IRS is withdrawn following sustained use.Methods and analysis This protocol follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A systematic search of studies published between 2000 and 2022 will be performed in CINAHL, Embase, MEDLINE, ProQuest, PsychInfo, Scopus and OpenGrey. Preset eligibility criteria will be used to identify studies for inclusion by two independent reviewers. Title/abstracts will first be screened and potentially eligible ones screened using their full-text publications. Any conflicts/discrepancies at the two stages will be resolved through regular discussion sessions. Included studies will be extracted to capture study and patient characteristics and relevant outcomes (malaria incidence and malaria vector abundance). Relevant tools will be used to assess the risk of bias in the studies measuring the impact of withdrawal. A meta-analysis will be performed if sufficient homogeneity exists; otherwise, data arising will be presented using tables and by employing narrative synthesis techniques. Heterogeneity will be assessed using a combination of visual inspection of the forest plot along with consideration of the χ2 test and I2 statistic results.Ethics and dissemination Ethics approval is not applicable for this study since no original data will be collected. The results will be disseminated through peer-reviewed publications and conference presentations. Furthermore, this systematic review will inform the design of exit strategies for IRS-based programmes in malaria-endemic areas.PROSPERO registration number CRD42022310655.