BACKGROUND:Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage renal disease with a high rate of recurrence after kidney transplantation. Several factors, such as white race, rapid progression, and previous allograft failure due to recurrence, were found to be risks of recurrence. Data are limited on the benefits of rituximab and/or therapeutic plasma exchange (TPE) in preventing recurrence. In this study, we sought to assess the efficacy of rituximab and TPE for the prevention and treatment of recurrent FSGS after kidney transplantation. METHODS:We enrolled 66 patients with FSGS in this prospective observational study and followed their outcomes. Patients with high risk for recurrence received preventative therapy with TPE and/or rituximab. RESULTS:Twenty-three (62%) of the 37 patients who received preventative therapy developed recurrence compared with 14 (51%) recurrences of the 27 patients who did not receive any therapy (P = 0.21). There was a trend for less relapse when rituximab was used as a therapy for recurrent FSGS (6/22 vs 9/18, P = 0.066). We used a clinical score of 5 values to assess the prediction of FSGS recurrence. A score of 3 or more had a predictive receiver operating characteristic curve of 0.72. Treatment with TPE and/or rituximab resulted in better allograft survival than historical studies. Allograft failure because of recurrent FSGS occurred in only 6 (9%) patients. CONCLUSIONS:Preventative therapies do not decrease the recurrence rate of recurrent FSGS. However, prompt treatment of recurrence with these therapies may result in improved outcomes.

Background

Cognitive impairment is common in kidney transplant (KT) recipients and affects quality of life, graft survival, morbidity, and mortality. Failure to identify patients with cognitive impairment can withhold appropriate and timely intervention. This study determines whether measured cognition with standard screening tools offers any advantage over perceived cognition in screening transplant patients for cognitive impairment.

Methods

Cognition was assessed in 157 KT recipients using the Montreal Cognitive Assessment (MoCA; measured cognition). In addition, transplant physicians and nurse coordinators were asked to rate transplant recipients' level of cognition after routine clinical interactions (perceived cognition). Physicians and nurses were blind to MoCA scores. Perceived cognition scores were compared to MoCA scores.

Results

Perceived cognition scores fairly correlated with MOCA scores (γ = 0.24, p = 0.001 for physicians and γ = 0.33, p < 0.0001 for nurses). Physician scores moderately correlated with nurses scores (κ = 0.44, p < 0.0001). Clinical perception had a low accuracy for identifying patients with cognitive impairment (sensitivity 66% for physicians, 65% for nurses), and those without cognitive impairment (specificity 67% for physicians, 76% for nurses).

Conclusion

Clinical perception is inaccurate at detecting cognitive impairment in KT recipients. Objective tests should be considered to screen KT recipients for cognitive impairment.

Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p < 0.0001) and no change in performance on an additional task (delayed logical memory). In this study, although insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important physiological differences between these cohorts.

With more than 10,000 mental health apps available, consumers and clinicians who want to adopt such tools can be overwhelmed by the multitude of options and lack of clear evaluative standards. Despite the increasing prevalence of curated lists, or app guides, challenges remain. Organizations providing mental health services to consumers have an opportunity to address these challenges by producing guides that meet relevant standards of quality and are tailored to local needs. This column summarizes an example of the collaborative process of app guide development in a publicly funded mental health service context and highlights opportunities and barriers identified through the process.

128 Background: LuPSMA, a radioligand therapy targeting the cell surface protein PSMA, is approved for men with PSMA-positive mCRPC previously treated with androgen receptor signaling inhibitor (ARSI) and taxane chemotherapy. Several PARP inhibitors (PARPi) are also currently approved for patients with mCRPC harboring alterations in genes associated with DNA damage repair (DDR). Given that both therapeutics result in DNA damage, we hypothesized that there would be clinical evidence of cross-resistance between the two classes of agents, with decreased efficacy in patients receiving LuPSMA following a PARPi. Methods: We abstracted retrospective data from patients at three centers who received at least one cycle of LuPSMA per the FDA label and had panel-based tumor sequencing performed. Patients with PARPi qualifying mutations were included in the analysis. PSA50 responses (i.e. ≥50% decline in PSA from baseline), PSA progression free survival (PFS) and overall survival (OS) following treatment with LuPSMA were compared between patients who received prior PARPi (PARPi-T cohort) and those who did not (PARPi-NT cohort). Results: Forty-nine patients with a PARPi qualifying alteration who received at least one cycle of LuPSMA were identified. Baseline characteristics (Gleason score, visceral metastases, race, ECOG PS, PSMA SUVmean/max) were similar between cohorts. Prior non-PARPi lines of therapy, including receipt of radium-223 (14% vs 21%), carboplatin (33% vs 36%), ≥ 2 prior ARSI (67% vs 68%), and ≥ 2 prior taxanes (43% vs 47%) were also similar between the PARP-NT and PARP-T cohorts respectively. Median PSA PFS and OS were both significantly increased in the PARPi-NT cohort as compared to the PARPi-T cohort (Table). PSA50 responses were numerically increased in the PARP-NT cohort, although this did not reach statistical significance. The most common PARPi qualifying alteration was BRCA2 (N=15). PARP-NT patients with BRCA2 alterations had significantly increased PSA PFS and OS as well as PSA50 response rates compared to the PARP-T patients. Conclusions: Prior receipt of PARPi therapy appears to negatively associate with the clinical activity of LuPSMA, with the largest difference in outcomes observed in patients with BRCA2 mutations. These data support the hypothesis that PARPi therapy may lead to clinically significant cross-resistance with LuPSMA. Prospective studies to evaluate the optimal sequence of LuPSMA and PARPi therapy are justified. [Table: see text]

With the development of modern solid-phase assays to detect anti-HLA antibodies and a more precise histological classification, the diagnosis of antibody-mediated rejection (AMR) has become more common and is a major cause of kidney graft loss. Currently, there are no approved therapies and treatment guidelines are based on low-level evidence. The number of prospective randomized trials for the treatment of AMR is small, and the lack of an accepted common standard for care has been an impediment to the development of new therapies. To help alleviate this, The Transplantation Society convened a meeting of international experts to develop a consensus as to what is appropriate treatment for active and chronic active AMR. The aim was to reach a consensus for standard of care treatment against which new therapies could be evaluated. At the meeting, the underlying biology of AMR, the criteria for diagnosis, the clinical phenotypes, and outcomes were discussed. The evidence for different treatments was reviewed, and a consensus for what is acceptable standard of care for the treatment of active and chronic active AMR was presented. While it was agreed that the aims of treatment are to preserve renal function, reduce histological injury, and reduce the titer of donor-specific antibody, there was no conclusive evidence to support any specific therapy. As a result, the treatment recommendations are largely based on expert opinion. It is acknowledged that properly conducted and powered clinical trials of biologically plausible agents are urgently needed to improve patient outcomes.

BACKGROUND:Anti-human leukocyte antigen donor-specific antibodies (anti-HLA DSAs) are recognized as a major barrier to patients' access to organ transplantation and the major cause of graft failure. The capacity of circulating anti-HLA DSAs to activate complement has been suggested as a potential biomarker for optimizing graft allocation and improving the rate of successful transplantations. METHODS AND FINDINGS:To address the clinical relevance of complement-activating anti-HLA DSAs across all solid organ transplant patients, we performed a meta-analysis of their association with transplant outcome through a systematic review, from inception to January 31, 2018. The primary outcome was allograft loss, and the secondary outcome was allograft rejection. A comprehensive search strategy was conducted through several databases (Medline, Embase, Cochrane, and Scopus). A total of 5,861 eligible citations were identified. A total of 37 studies were included in the meta-analysis. Studies reported on 7,936 patients, including kidney (n = 5,991), liver (n = 1,459), heart (n = 370), and lung recipients (n = 116). Solid organ transplant recipients with circulating complement-activating anti-HLA DSAs experienced an increased risk of allograft loss (pooled HR 3.09; 95% CI 2.55-3.74, P = 0.001; I2 = 29.3%), and allograft rejection (pooled HR 3.75; 95% CI: 2.05-6.87, P = 0.001; I2 = 69.8%) compared to patients without complement-activating anti-HLA DSAs. The association between circulating complement-activating anti-HLA DSAs and allograft failure was consistent across all subgroups and sensitivity analyses. Limitations of the study are the observational and retrospective design of almost all included studies, the higher proportion of kidney recipients compared to other solid organ transplant recipients, and the inclusion of fewer studies investigating allograft rejection. CONCLUSIONS:In this study, we found that circulating complement-activating anti-HLA DSAs had a significant deleterious impact on solid organ transplant survival and risk of rejection. The detection of complement-activating anti-HLA DSAs may add value at an individual patient level for noninvasive biomarker-guided risk stratification. TRIAL REGISTRATION:National Clinical Trial protocol ID: NCT03438058.

Thirty percent of kidney transplant recipients are readmitted in the first month posttransplantation. Those with donor-specific antibody requiring desensitization and incompatible live donor kidney transplantation (ILDKT) constitute a unique subpopulation that might be at higher readmission risk. Drawing on a 22-center cohort, 379 ILDKTs with Medicare primary insurance were matched to compatible transplant-matched controls and to waitlist-only matched controls on panel reactive antibody, age, blood group, renal replacement time, prior kidney transplantation, race, gender, diabetes, and transplant date/waitlisting date. Readmission risk was determined using multilevel, mixed-effects Poisson regression. In the first month, ILDKTs had a 1.28-fold higher readmission risk than compatible controls (95% confidence interval [CI] 1.13-1.46; P < .001). Risk peaked at 6-12 months (relative risk [RR] 1.67, 95% CI 1.49-1.87; P < .001), attenuating by 24-36 months (RR 1.24, 95% CI 1.10-1.40; P < .001). ILDKTs had a 5.86-fold higher readmission risk (95% CI 4.96-6.92; P < .001) in the first month compared to waitlist-only controls. At 12-24 (RR 0.85, 95% CI 0.77-0.95; P = .002) and 24-36 months (RR 0.74, 95% CI 0.66-0.84; P < .001), ILDKTs had a lower risk than waitlist-only controls. These findings of ILDKTs having a higher readmission risk than compatible controls, but a lower readmission risk after the first year than waitlist-only controls should be considered in regulatory/payment schemas and planning clinical care.

Importance

SARS-CoV-2 entry requires the TMPRSS2 cell surface protease. Antiandrogen therapies reduce expression of TMPRSS2.

Objective

To determine if temporary androgen suppression induced by degarelix improves clinical outcomes of inpatients hospitalized with COVID-19.

Design, setting, and participants

The Hormonal Intervention for the Treatment in Veterans With COVID-19 Requiring Hospitalization (HITCH) phase 2, placebo-controlled, double-blind, randomized clinical trial compared efficacy of degarelix plus standard care vs placebo plus standard care on clinical outcomes in men hospitalized with COVID-19 but not requiring invasive mechanical ventilation. Inpatients were enrolled at 14 Department of Veterans Affairs hospitals from July 22, 2020, to April 8, 2021. Data were analyzed from August 9 to October 15, 2021.

Interventions

Patients stratified by age, history of hypertension, and disease severity were centrally randomized 2:1 to degarelix, (1-time subcutaneous dose of 240 mg) or a saline placebo. Standard care included but was not limited to supplemental oxygen, antibiotics, vasopressor support, peritoneal dialysis or hemodialysis, intravenous fluids, remdesivir, convalescent plasma, and dexamethasone.

Main outcomes and measures

The composite primary end point was mortality, ongoing need for hospitalization, or requirement for mechanical ventilation at day 15 after randomization. Secondary end points were time to clinical improvement, inpatient mortality, length of hospitalization, duration of mechanical ventilation, time to achieve a temperature within reference range, maximum severity of COVID-19, and the composite end point at 30 days.

Results

The trial was stopped for futility after the planned interim analysis, at which time there were 96 evaluable patients, including 62 patients randomized to the degarelix group and 34 patients in the placebo group, out of 198 initially planned. The median (range) age was 70.5 (48-85) years. Common comorbidities included chronic obstructive pulmonary disorder (15 patients [15.6%]), hypertension (75 patients [78.1%]), cardiovascular disease (27 patients [28.1%]), asthma (12 patients [12.5%]), diabetes (49 patients [51.0%]), and chronic respiratory failure requiring supplemental oxygen at baseline prior to COVID-19 (9 patients [9.4%]). For the primary end point, there was no significant difference between the degarelix and placebo groups (19 patients [30.6%] vs 9 patients [26.5%]; P = .67). Similarly, no differences were observed between degarelix and placebo groups in any secondary end points, including inpatient mortality (11 patients [17.7%] vs 6 patients [17.6%]) or all-cause mortality (11 patients [17.7%] vs 7 patents [20.6%]). There were no differences between degarelix and placebo groups in the overall rates of adverse events (13 patients [21.0%] vs 8 patients [23.5%) and serious adverse events (19 patients [30.6%] vs 13 patients [32.4%]), nor unexpected safety concerns.

Conclusions and relevance

In this randomized clinical trial of androgen suppression vs placebo and usual care for men hospitalized with COVID-19, degarelix did not result in amelioration of COVID-19 severity.

Trial registration

ClinicalTrials.gov Identifier: NCT04397718.