Proteinuria Reduction and Kidney Survival in Focal Segmental Glomerulosclerosis.

RATIONALE & OBJECTIVE: Remission of proteinuria has been shown to be associated with lower rates of kidney disease progression among people with focal segmental glomerulosclerosis (FSGS). The goal of this study was to evaluate whether reductions in proteinuria after treatment are associated with greater kidney survival. STUDY DESIGN: Cohort analysis of clinical trial participants. SETTING & PARTICIPANTS: Patients with steroid-resistant FSGS enrolled in a randomized treatment trial that compared cyclosporine with mycophenolate mofetil plus dexamethasone. PREDICTORS: Reduction in proteinuria measured during 26 weeks after initiating treatment. OUTCOMES: Repeated assessments of estimated glomerular filtration rate (eGFR) and time to a composite outcome of kidney failure or death assessed between 26 weeks and 54 months after randomization. ANALYTICAL APPROACH: Multivariable linear mixed-effects models with participant-specific slope and intercept to estimate the association of change in proteinuria over 26 weeks while receiving treatment with the subsequent slope of change in eGFR. Multivariable time-varying Cox proportional hazards models were used to estimate the association of changes in proteinuria with time to the composite outcome. RESULTS: 138 of 192 trial participants were included. Changes in proteinuria over 26 weeks were significantly related to eGFR slope. A 1-unit reduction in log-transformed urinary protein-creatinine ratio was associated with a 3.90mL/min/1.73m2 per year increase in eGFR (95% CI, 2.01-5.79). This difference remained significant after adjusting for complete remission. There was an analogous relationship between time-varying proteinuria and time to the composite outcome: the HR per 1-unit reduction in log-transformed urinary protein-creatinine ratio was 0.23 (95% CI, 0.12-0.44). LIMITATIONS: Limited to individuals with steroid-resistant FSGS followed up for a maximum of 5 years. CONCLUSIONS: These findings provide evidence for the benefit of urinary protein reduction in FSGS. Reductions in proteinuria warrant further evaluation as a potential surrogate for preservation of kidney function that may inform the design of future clinical trials.

Cryoablation Without Excision for Low-Risk Early-Stage Breast Cancer: 3-Year Interim Analysis of Ipsilateral Breast Tumor Recurrence in the ICE3 Trial.

BACKGROUND: The ICE3 trial is designed to evaluate the safety and efficacy of breast cryoablation, enabling women older than 60 years with low-risk early-stage breast cancers to benefit from a nonsurgical treatment and to avoid the associated surgical risks. METHODS: The ICE3 trial is a prospective, multi-center, single-arm, non-randomized trial including women age 60 years or older with unifocal, ultrasound-visible invasive ductal carcinoma size 1.5 cm or smaller and classified as low to intermediate grade, hormone receptor (HR)-positive, and human epidermal growth factor receptor 2 (HER2)-negative. Ipsilateral breast tumor recurrence (IBTR) at 5 years was the primary outcome. A 3-year interim analysis of IBTR was performed, and the IBTR probability was estimated using the Kaplan-Meier method. RESULTS: Full eligibility for the study was met by 194 patients, who received successful cryoablation per protocol. The mean age was 75 years (range, 55-94 years). The mean tumor length was 8.1 mm (range, 8-14.9 mm), and the mean tumor width was 7.4 mm (range, 2.8-14 mm). During a mean follow-up period of 34.83 months, the IBTR rate was 2.06% (4/194 patients). Device-related adverse events were reported as mild in 18.4% and moderate in 2.4% of the patients. No severe device-related adverse events were reported. More than 95% of the patients and 98% of the physicians reported satisfaction with the cosmetic results at the clinical follow-up evaluation. CONCLUSIONS: Breast cryoablation presents a promising alternative to surgery while offering the benefits of a minimally invasive procedure with minimal risks. Further study within a clinical trial or registry is needed to confirm cryoablation as a viable alternative to surgical excision for appropriately selected low-risk patients.

Association of a de novo nonsense mutation of the TRIM8 gene with childhood-onset focal segmental glomerulosclerosis.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is an etiologically heterogeneous disorder. Genetic FSGS may be either limited to the kidney or part of a genetic syndrome with other systemic involvement. At least 21 and 34 genes have been reported for renal-limited and syndromic FSGS, respectively. The TRIM8 gene encodes a tripartite motif protein, which is an E3 ubiquitin-protein ligase that promotes proteasomal degradation of the suppressor of cytokine signaling 1 (SOCS1) and participates in the activation of interferon-gamma signaling. The TRIM8 gene is expressed in various tissues including the kidney and the central nervous system (CNS). An association between a mutation in the TRIM8 gene and childhood-onset FSGS has not been well established. CASE-DIAGNOSIS: We describe an 8-year-old Hispanic male with infantile onset motor and developmental delay, seizures, and proteinuria secondary to FSGS. Next generation sequencing revealed a heterozygous de novo pathogenic variant in the TRIM8 gene (C1380T>A, p.Tyr460*). Immunohistochemical staining using anti-TRIM8 and anti-SOCS1 antibodies showed no significant TRIM8 expression and strong expression of SOCS1 in the renal biopsy tissue. TREATMENT AND CONCLUSIONS: De novo truncating mutations of TRIM8 have been previously reported in childhood-onset epileptic encephalopathy. A molecular analysis of TRIM8 should be considered in children with FSGS and clinical abnormalities of the central nervous system.

Postmastectomy Radiotherapy: An American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Focused Guideline Update.

PURPOSE: A joint American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology panel convened to develop a focused update of the American Society of Clinical Oncology guideline concerning use of postmastectomy radiotherapy (PMRT). METHODS: A recent systematic literature review by Cancer Care Ontario provided the primary evidentiary basis. The joint panel also reviewed targeted literature searches to identify new, potentially practice-changing data. RECOMMENDATIONS: The panel unanimously agreed that available evidence shows that PMRT reduces the risks of locoregional failure (LRF), any recurrence, and breast cancer mortality for patients with T1-2 breast cancer with one to three positive axillary nodes. However, some subsets of these patients are likely to have such a low risk of LRF that the absolute benefit of PMRT is outweighed by its potential toxicities. In addition, the acceptable ratio of benefit to toxicity varies among patients and physicians. Thus, the decision to recommend PMRT requires a great deal of clinical judgment. The panel agreed clinicians making such recommendations for individual patients should consider factors that may decrease the risk of LRF, attenuate the benefit of reduced breast cancer-specific mortality, and/or increase risk of complications resulting from PMRT. When clinicians and patients elect to omit axillary dissection after a positive sentinel node biopsy, the panel recommends that these patients receive PMRT only if there is already sufficient information to justify its use without needing to know additional axillary nodes are involved. Patients with axillary nodal involvement after neoadjuvant systemic therapy should receive PMRT. The panel recommends treatment generally be administered to both the internal mammary nodes and the supraclavicular-axillary apical nodes in addition to the chest wall or reconstructed breast.

Kidney retransplantation in children following rejection and recurrent disease.

Retransplantation accounts for approximately 15 % of the annual transplants performed in the USA, and in the recent International Collaborative Transplant Study report on pediatric patients 15.2 % of the 9209 patients included in the report were retransplant recipients. Although the significant advances in clinical management and newer immunosuppressive agents have had a significant impact on improving short-term allograft function, it is apparent that long-term allograft function remains suboptimal. Therefore, it is likely that the majority of pediatric renal allograft recipients will require one or more retransplants during their lifetime. Unfortunately, a second or subsequent graft in pediatric recipients has inferior long-term graft survival rates compared to initial grafts, with decreasing rates with each subsequent graft. Multiple issues influence the outcome of retransplantation, with the most significant being the cause of the prior transplant failure. Non-adherence-associated graft loss poses unresolved ethical issues that may impact access to retransplantation. Graft nephrectomy prior to retransplantation may benefit selected patients, but the impact of an in situ failed graft on the development of panel-reactive antibodies remains to be definitively determined. It is important that these and other factors discussed in this review be taken into consideration during the counseling of families on the optimal approach for their child who requires a retransplant.

Alemtuzumab with corticosteroid minimization for pediatric deceased donor renal transplantation: a seven-yr experience.

Alemtuzumab is a monoclonal antibody targeting CD52 receptors on B and T lymphocytes and is an effective induction agent in pediatric renal transplantation. We report a seven-yr experience using alemtuzumab induction and steroid-free protocol in the pediatric population as safe and effective. Twenty-one pediatric deceased donor renal transplants were performed at a single academic institution. All received induction with single-dose alemtuzumab and were maintained on a steroid-free protocol using TAC and MMF immunosuppression. There were 15 males and six females in the study whose ages ranged from one to 19 yr. The average follow-up was 32 months (range from 12 to 78.2 months and median 33.7 ± 23.7 months). All patients had immediate graft function. Graft survival was 95%, and patient survival was 100%. Mean 12 and 36 months eGFR were 63.33 ± 21.01 and 59.90 ± 15.27 mL/min/1.73m(2), respectively. Three patients developed acute T-cell-mediated rejection due to non-adherence while no recipients developed cytomegalovirus infection, PTLD, or polyoma BK viral nephropathy. Steroid avoidance with single-dose alemtuzumab induction provides adequate and safe immunosuppression in pediatric deceased donor renal transplant recipients receiving TAC and low-dose MMF maintenance therapy.

Solid organ transplantation following end-organ failure in recipients of hematopoietic stem cell transplantation in children.

Hematopoietic stem cell transplantation (HSCT) is an accepted treatment modality for various malignant and non-malignant disorders of the lympho-hematopoietic system. Patient survival rate has increased significantly with the use of this procedure. However, with the increase in disease-free patient survival rates, complications including various organ toxicities are also common. Kidney, liver, lung, heart, and skin are among those solid organs that are commonly affected and frequently lead to organ dysfunction and eventually end-organ disease. Conservative measures may or may not be successful in managing the organ failure in these patients. Solid organ transplantation has been shown to be promising in those patients who fail conservative management. This review will summarize the causes of solid organ (kidney, liver, and lung) dysfunction and the available data on transplantation of these solid organs in post-HSCT recipients.

Growth hormone treatment after renal transplantation: a promising but underused chance to improve growth.

Growth retardation remains a clinical problem in children with chronic kidney disease (CKD) prior to and during end-stage renal disease. The growth of approximately 40 % of children on dialysis is stunted. Even so, growth hormone treatment (GH) is not used in the majority of small children prior to transplantation. Also, GH is effective in improving growth after transplantation, but again, it is only rarely used in this situation mainly for fear of triggering rejection episodes. In controlled studies, the number of patients who developed rejection episodes with GH was no greater than the number in untreated controls. However, patients with prior frequent rejection episodes developed further repeated subsequent rejection episodes. Many patients with repeated rejection episodes before GH treatment have reduced renal function and are expected to proceed to dialysis or retransplantation. We believe that in these patients, early individual decisions for or against GH treatment should be made as soon as other treatment strategies, such as steroid withdrawal, have failed or are not indicated. Decisions for GH treatment at a later pubertal age come too late for significant growth response and/or improvement of final height.

Molecular mechanism of the sweet taste enhancers.

Positive allosteric modulators of the human sweet taste receptor have been developed as a new way of reducing dietary sugar intake. Besides their potential health benefit, the sweet taste enhancers are also valuable tool molecules to study the general mechanism of positive allosteric modulations of T1R taste receptors. Using chimeric receptors, mutagenesis, and molecular modeling, we reveal how these sweet enhancers work at the molecular level. Our data argue that the sweet enhancers follow a similar mechanism as the natural umami taste enhancer molecules. Whereas the sweeteners bind to the hinge region and induce the closure of the Venus flytrap domain of T1R2, the enhancers bind close to the opening and further stabilize the closed and active conformation of the receptor.

Incentives for organ donation: proposed standards for an internationally acceptable system.

Incentives for organ donation, currently prohibited in most countries, may increase donation and save lives. Discussion of incentives has focused on two areas: (1) whether or not there are ethical principles that justify the current prohibition and (2) whether incentives would do more good than harm. We herein address the second concern and propose for discussion standards and guidelines for an acceptable system of incentives for donation. We believe that if systems based on these guidelines were developed, harms would be no greater than those to today's conventional donors. Ultimately, until there are trials of incentives, the question of benefits and harms cannot be satisfactorily answered.

Tumor bed control with balloon-based accelerated partial breast irradiation: incidence of true recurrences versus elsewhere failures in the American Society of Breast Surgery MammoSite(®) Registry Trial.

BACKGROUND: Randomized trials demonstrate that lumpectomy plus whole-breast irradiation (WBI) yields survival equivalent to mastectomy. Studies that use WBI, however, typically report higher tumor bed recurrence rates than elsewhere failures (EF) (historically considered new primary lesions). The rate of true recurrence (TR) versus EF was queried for a large patient cohort treated with accelerated partial breast irradiation (APBI). METHODS: A total of 1,449 cases of early-stage breast cancer were treated on the American Society of Breast Surgeons MammoSite(®) Registry Trial with lumpectomy plus balloon-based APBI (34 Gy, 10 BID fractions). A total of 1,255 cases (87 %) had invasive breast cancer, and 194 patients (13 %) had ductal carcinoma in situ. Rates of TR versus EF were calculated and compared to historical WBI controls. RESULTS: Median follow-up was 60 (range 0-109) months. Fifty patients (3.5 %) developed an ipsilateral breast tumor recurrence (IBTR). The 5-year actuarial rate of IBTR was 3.6 % (invasive breast cancer 3.6 %, ductal carcinoma in situ 3.4 %). Fourteen IBTR (1.1 %) were TR, while 36 (2.6 %) were EF. Estrogen receptor-negative status was associated with IBTR for invasive malignancies as well as for EF only (p < 0.001). Trends for increased rates of EF were noted for increased tumor size (p = 0.067) and extensive intraductal component (p = 0.087). No pathologic factors were explicitly associated with TR. CONCLUSIONS: IBTR after balloon-based APBI is low and similar to rates reported for WBI. In this data set, APBI had fewer tumor bed recurrences (presumably initial cancer recurrences) than EF (presumably new primary lesions). This suggests that balloon-based APBI has a tumor bed control rate that is at least equal to (and potentially higher than) WBI.

Comparing Kidney Health Outcomes in Children, Adolescents, and Adults With Focal Segmental Glomerulosclerosis.

Importance: Focal segmental glomerulosclerosis (FSGS) is a common cause of end-stage kidney disease (ESKD) across the lifespan. While 10% to 15% of children and 3% of adults who develop ESKD have FSGS, it remains uncertain whether the natural history differs in pediatric vs adult patients, and this uncertainty contributes to the exclusion of children and adolescents in clinical trials. Objective: To examine whether there are differences in the kidney health outcomes among children, adolescents, and adults with FSGS. Design, Setting, and Participants: This cohort study used pooled and parallel analyses, completed July 5, 2022, from 3 complimentary data sources: (1) Nephrotic Syndrome Rare Disease Clinical Research Network (NEPTUNE); (2) FSGS clinical trial (FSGS-CT); and (3) Kidney Research Network (KRN). NEPTUNE is a multicenter US/Canada cohort study; FSGS-CT is a multicenter US/Canada clinical trial; and KRN is a multicenter US electronic health record-based registry from academic and community nephrology practices. NEPTUNE included 166 patients with incident FSGS enrolled at first kidney biopsy; FSGS-CT included 132 patients with steroid-resistant FSGS randomized to cyclosporine vs dexamethasone with mycophenolate; and KRN included 184 patients with prevalent FSGS. Data were collected from November 2004 to October 2019 and analyzed from October 2020 to July 2022. Exposures: Age: children (age <13 years) vs adolescents (13-17 years) vs adults (≥18 years). Covariates of interest included sex, disease duration, APOL1 genotype, urine protein-to-creatinine ratio, estimated glomerular filtration rate (eGFR), edema, serum albumin, and immunosuppressive therapy. Main Outcomes and Measures: ESKD, composite outcome of ESKD or 40% decline in eGFR, and complete and/or partial remission of proteinuria. Results: The study included 127 (26%) children, 102 (21%) adolescents, and 253 (52%) adults, including 215 (45%) female participants and 138 (29%) who identified as Black, 98 (20%) who identified as Hispanic, and 275 (57%) who identified as White. Overall, the median time to ESKD was 11.9 years (IQR, 5.2-19.1 years). There was no difference in ESKD risk among children vs adults (hazard ratio [HR], 0.67; 95% CI, 0.43-1.03) or adolescents vs adults (HR, 0.85; 95% CI, 0.52-1.36). The median time to the composite end point was 5.7 years (IQR 1.6-15.2 years), with hazard ratio estimates for children vs adults of 1.12 (95% CI, 0.83-1.52) and adolescents vs adults of 1.06 (95% CI, 0.75-1.50). Conclusions and Relevance: In this study, the association of FSGS with kidney survival and functional outcomes was comparable at all ages.

Retromer disruption promotes amyloidogenic APP processing.

Retromer deficiency has been implicated in sporadic AD and animals deficient in retromer components exhibit pronounced neurodegeneration. Because retromer performs retrograde transport from the endosome to the Golgi apparatus and neuronal Aß is found in late endosomal compartments, we speculated that retromer malfunction might enhance amyloidogenic APP processing by promoting interactions between APP and secretase enzymes in late endosomes. We have evaluated changes in amyloid precursor protein (APP) processing and trafficking as a result of disrupted retromer activity by knockdown of Vps35, a vacuolar sorting protein that is an essential component of the retromer complex. Knocking down retromer activity produced no change in the quantity or cellular distribution of total cellular APP and had no affect on internalization of cell-surface APP. Retromer deficiency did, however, increase the ratio of secreted Aß42:Aß40 in HEK-293 cells over-expressing APP695, due primarily to a decrease in Aß40 secretion. Recent studies suggest that the retromer-trafficked protein, Wntless, is secreted at the synapse in exosome vesicles and that these same vesicles contain Aß. We therefore hypothesized that retromer deficiency may be associated with altered exosomal secretion of APP and/or secretase fragments. Holo-APP, Presenilin and APP C-terminal fragments were detected in exosomal vesicles secreted from HEK-293 cells. Levels of total APP C-terminal fragments were significantly increased in exosomes secreted by retromer deficient cells. These data suggest that reduced retromer activity can mimic the effects of familial AD Presenilin mutations on APP processing and promote export of amyloidogenic APP derivatives.

Clinical trial of focal segmental glomerulosclerosis in children and young adults.

This NIH-funded multicenter randomized study of focal segmental glomerulosclerosis (FSGS) treatment compared the efficacy of a 12-month course of cyclosporine to a combination of oral pulse dexamethasone and mycophenolate mofetil in children and adults with steroid-resistant primary FSGS. Of the 192 patients enrolled, 138 were randomized to cyclosporine (72) or to mycophenolate/dexamethasone (66). The primary analysis compared the levels of an ordinal variable measuring remission during the first year. The odds ratio (0.59) for achieving at least a partial remission with mycophenolate/dexamethasone compared to cyclosporine was not significant. Partial or complete remission was achieved in 22 mycophenolate/dexamethasone- and 33 cyclosporine-treated patients at 12 months. The main secondary outcome, preservation of remission for 26 weeks following cessation of treatment, was not significantly different between these two therapies. During the entire 78 weeks of study, 8 patients treated with cyclosporine and 7 with mycophenolate/dexamethasone died or developed kidney failure. Thus, our study did not find a difference in rates of proteinuria remission following 12 months of cyclosporine compared to mycophenolate/dexamethasone in patients with steroid-resistant FSGS. However, the small sample size might have prevented detection of a moderate treatment effect.

Clinical trials treating focal segmental glomerulosclerosis should measure patient quality of life.

Optimal therapy of patients with steroid-resistant primary focal segmental glomerulosclerosis (FSGS) remains controversial. This report describes the initial study design, baseline characteristics, and quality of life of patients enrolled in the FSGS Clinical Trial, a large multicenter randomized study of this glomerulopathy comparing a 12-month regimen of cyclosporine to the combination of mycophenolate mofetil and oral dexamethasone. Patients with age ranging 2-40 years, with an estimated glomerular filtration rate > 40 ml/min per 1.73 m², a first morning urine protein-to-creatinine ratio over one, and resistant to corticosteroids were eligible. The primary outcome was complete or partial remission of proteinuria over 52 weeks after randomization. In all, 192 patients were screened, of whom 138 were randomized for treatment. Ethnic distributions were 53 black, 78 white, and 7 other. By self- or parent-proxy reporting, 26 of the 138 patients were identified as Hispanic. The baseline glomerular filtration rate was 112.4 (76.5, 180.0) ml/min per 1.73 m², and urine protein was 4.0 (2.1, 5.3) g/g. Overall, the quality of life of the patients with FSGS was lower than healthy controls and similar to that of patients with end-stage renal disease. Thus, the impact of FSGS on quality of life is significant and this measurement should be included in all trials.

Axillary failure in patients treated with MammoSite accelerated partial breast irradiation.

BACKGROUND: The risk of axillary failure (AF) after accelerated partial breast irradiation (APBI) using MammoSite brachytherapy is unknown and has been source of concern as the axillary region is not treated with this technique. We aimed to determine the rate of AF in patients treated with APBI and identify factors associated with its occurrence. METHODS: Data from the American Society of Breast Surgeons MammoSite Registry Trial were reviewed and patients with AF were identified. Clinical, pathologic and treatment-related variables were analyzed to determine which factors were associated with AF. RESULTS: A total of 1440 patients underwent MammoSite APBI. A total of 1449 cases were treated (9 patients received bilateral treatment), 1255 cases (87%) of invasive breast cancer and 194 cases (13%) of ductal carcinoma in situ (DCIS). The median length of follow-up was 59 months. There were 10 patients who had an AF. Of these, 9 patients had an initial diagnosis of invasive cancer and 1 had an initial diagnosis of DCIS. The 5-year actuarial rate of AF was 0.79%. The only independent risk factor for AF identified by multivariate analysis was the presence of high-grade disease (P=.008). The 5-year overall survival rate in patients with an AF was 77.8% (there was 1 death related to breast cancer). CONCLUSIONS: The rate of AF after MammoSite APBI is low and appears to be similar to that achieved with whole-breast irradiation.

Molecular mechanism for the umami taste synergism.

Umami is one of the 5 basic taste qualities. The umami taste of L-glutamate can be drastically enhanced by 5' ribonucleotides and the synergy is a hallmark of this taste quality. The umami taste receptor is a heteromeric complex of 2 class C G-protein-coupled receptors, T1R1 and T1R3. Here we elucidate the molecular mechanism of the synergy using chimeric T1R receptors, site-directed mutagenesis, and molecular modeling. We propose a cooperative ligand-binding model involving the Venus flytrap domain of T1R1, where L-glutamate binds close to the hinge region, and 5' ribonucleotides bind to an adjacent site close to the opening of the flytrap to further stabilize the closed conformation. This unique mechanism may apply to other class C G-protein-coupled receptors.

Diamino-1,2,4-triazole derivatives are selective inhibitors of TYK2 and JAK1 over JAK2 and JAK3.

Tyrosine kinase 2 (TYK2) is required for signaling of interleukin-23 (IL-23), which plays a key role in rheumatoid arthritis. Presented is the design and synthesis of 1,2,4-triazoles, and the evaluation of their inhibitory activity against the Janus associated kinases TYK2 and JAKs 1-3.