Unveiling renal pathology's potential: exploring a rare subtype of amyloid - apolipoprotein CII amyloidosis in the youngest patient: a case report and literature review.

In this clinical case report, we present a rare subtype of amyloidosis, apolipoprotein CII (apo CII), which was diagnosed through a renal biopsy and subsequently confirmed by identifying the p.K41T mutation via germline DNA sequencing. Upon reviewing the literature, five patients exhibiting identical mutation were identified via renal biopsy, while an additional patient was diagnosed through biopsies of the fat pad and bone marrow. Notably, our patient is the youngest recorded case. We pioneered the application of immunofluorescence and immunogold electron microscopy techniques for apo CII evaluation. Our report provides a detailed description of this case, supplemented by an extensive review encompassing apo CII, documented instances of apo CII amyloidosis with renal or systemic involvement, and potential underlying mechanisms.

Mycophenolate mofetil withdrawal in patients with systemic lupus erythematosus: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Mycophenolate mofetil is an immunosuppressant commonly used to treat systemic lupus erythematosus (SLE) and lupus nephritis. It is a known teratogen associated with significant toxicities, including an increased risk of infections and malignancies. Mycophenolate mofetil withdrawal is desirable once disease quiescence is reached, but the timing of when to do so and whether it provides a benefit has not been well-studied. We aimed to determine the effects of mycophenolate mofetil withdrawal on the risk of clinically significant disease reactivation in patients with quiescent SLE on long-term mycophenolate mofetil therapy. METHODS: This multicenter, open-label, randomised trial was conducted in 19 centres in the USA. Eligible patients were aged between 18 and 70 years old, met the American College of Rheumatology (ACR) 1997 SLE criteria, and had a clinical SLEDAI score of less than 4 at screening. Mycophenolate mofetil therapy was required to be stable or decreasing for 2 years or more if initiated for renal indications, or for 1 year or more for non-renal indications. Participants were randomly allocated in a 1:1 ratio to a withdrawal group, who tapered off mycophenolate mofetil over 12 weeks, or a maintenance group who maintained their baseline dose (1-3g per day) for 60 weeks. Adaptive random allocation ensured groups were balanced for study site, renal versus non-renal disease, and baseline mycophenolate mofetil dose (≥2 g per day vs <2 g per day). Clinically significant disease reactivation by week 60 following random allocation, requiring increased doses or new immunosuppressive therapy was the primary endpoint, in the modified intention-to-treat population (all randomly allocated participants who began study-provided mycophenolate mofetil). Non-inferiority was evaluated using an estimation-based approach. The trial was registered at ClinicalTrials.gov (NCT01946880) and is completed. FINDINGS: Between Nov 6, 2013, and April 27, 2018, 123 participants were screened, of whom 102 were randomly allocated to the maintenance group (n=50) or the withdrawal group (n=52). Of the 100 participants included in the modified intention-to-treat analysis (49 maintenance, 51 withdrawal), 84 (84%) were women, 16 (16%) were men, 40 (40%) were White, 41 (41%) were Black, and 76 (76%) had a history of lupus nephritis. The average age was 42 (SD 12·7). By week 60, nine (18%) of 51 participants in the withdrawal group had clinically significant disease reactivation, compared to five (10%) of 49 participants in the maintenance group. The risk of clinically significant disease reactivation was 11% (95% CI 5-24) in the maintenance group and 18% (10-32) in the withdrawal group. The estimated increase in the risk of clinically significant disease reactivation with mycophenolate mofetil withdrawal was 7% (one-sided upper 85% confidence limit 15%). Similar rates of adverse events were observed in the maintenance group (45 [90%] of 50 participants) and the withdrawal group (46 [88%] of 52 participants). Infections were more frequent in the mycophenolate mofetil maintenance group (32 [64%]) compared with the withdrawal group (24 [46%]). INTERPRETATIONS: Mycophenolate mofetil withdrawal is not significantly inferior to mycophenolate mofetil maintenance. Estimates for the rates of disease reactivation and increases in risk with withdrawal can assist clinicians in making informed decisions on withdrawing mycophenolate mofetil in patients with stable SLE. FUNDING: The National Institute of Allergy and Infectious Diseases and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.

A Canadian Survey of Research on HIV-1 Latency-Where Are We Now and Where Are We Heading?

Worldwide, almost 40 million people are currently living with HIV-1. The implementation of cART inhibits HIV-1 replication and reduces viremia but fails to eliminate HIV-1 from latently infected cells. These cells are considered viral reservoirs from which HIV-1 rebounds if cART is interrupted. Several efforts have been made to identify these cells and their niches. There has been little success in diminishing the pool of latently infected cells, underscoring the urgency to continue efforts to fully understand how HIV-1 establishes and maintains a latent state. Reactivating HIV-1 expression in these cells using latency-reversing agents (LRAs) has been successful, but only in vitro. This review aims to provide a broad view of HIV-1 latency, highlighting Canadian contributions toward these aims. We will summarize the research efforts conducted in Canadian labs to understand the establishment of latently infected cells and how this informs curative strategies, by reviewing how HIV latency is established, which cells are latently infected, what methodologies have been developed to characterize them, how new compounds are discovered and evaluated as potential LRAs, and what clinical trials aim to reverse latency in people living with HIV (PLWH).

Heterogeneous nuclear ribonucleoprotein K promotes cap-independent translation initiation of retroviral mRNAs.

Translation initiation of the human immunodeficiency virus-type 1 (HIV-1) genomic mRNA (vRNA) is cap-dependent or mediated by an internal ribosome entry site (IRES). The HIV-1 IRES requires IRES-transacting factors (ITAFs) for function. In this study, we evaluated the role of the heterogeneous nuclear ribonucleoprotein K (hnRNPK) as a potential ITAF for the HIV-1 IRES. In HIV-1-expressing cells, the depletion of hnRNPK reduced HIV-1 vRNA translation. Furthermore, both the depletion and overexpression of hnRNPK modulated HIV-1 IRES activity. Phosphorylations and protein arginine methyltransferase 1 (PRMT1)-induced asymmetrical dimethylation (aDMA) of hnRNPK strongly impacted the protein's ability to promote the activity of the HIV-1 IRES. We also show that hnRNPK acts as an ITAF for the human T cell lymphotropic virus-type 1 (HTLV-1) IRES, present in the 5'UTR of the viral sense mRNA, but not for the IRES present in the antisense spliced transcript encoding the HTLV-1 basic leucine zipper protein (sHBZ). This study provides evidence for a novel role of the host hnRNPK as an ITAF that stimulates IRES-mediated translation initiation for the retroviruses HIV-1 and HTLV-1.

Relationships among Non-Neoplastic Histopathological Features, Kidney Function, Proteinuria, and Other Clinical Factors in Patients Undergoing Nephrectomy.

Introduction: The non-neoplastic kidney parenchyma from nephrectomies is often overlooked in routine examinations. We aimed to evaluate the associations between global glomerulosclerosis (GS), interstitial fibrosis (IF), or arteriosclerosis (AS) and estimated glomerular filtration rate (eGFR), dipstick proteinuria, and other clinical factors. Methods: We performed a cross-sectional analysis of 781 patients with nephrectomy. We used regression models with and without interaction factors. The tested exposures were GS, IF, or AS, and the outcome measures were GFR and dipstick proteinuria. Results: In multivariable analyses, increasing degrees of GS, IF, or AS were significantly associated with lower eGFR and proteinuria (p < 0.05 for each). Obesity and hypertension (HTN) modified the association between eGFR and degrees of GS, whereas proteinuria and cardiovascular disease (CVD) modified the association between eGFR and degrees of AS (p for interaction <0.05). Compared with GS <10%, GS >50% was associated with lower eGFR in patients with (-45 mL/min/1.73 m2) than without (-19 mL/min/1.73 m2) obesity, and GS >50% was associated with lower eGFR in patients with (-31 mL/min/1.73 m2) than without (-16 mL/min/1.73 m2) HTN. Compared with AS <26%, AS >50% was associated with lower eGFR in patients with (-11 mL/min/1.73 m2) than without (-6 mL/min/1.73 m2) proteinuria, and AS >50% was associated with lower eGFR in patients with (-23 mL/min/1.73 m2) than without (-7 mL/min/1.73 m2) CVD. Conclusion: Greater degrees of each GS, IF, and AS are independently associated with proteinuria and lower eGFR. Obesity, HTN, proteinuria, and CVD modify the relationship between eGFR and specific histopathological features of nephrosclerosis.

Associations Between Albuminuria and Mortality Among US Adults by Demographic and Comorbidity Factors.

Background Albuminuria is a known marker of mortality risk. Whether the association between albuminuria and mortality differs by demographic and comorbidity factors remains unclear. Therefore, we sought to determine whether albuminuria is differentially associated with mortality. Methods and Results This study included 49 640 participants from the National Health and Nutrition Examination Survey (1999-2018). All-cause mortality through 2019 was linked from the National Death Index. Multivariable-adjusted Poisson regression models were used to determine whether levels of urine albumin-to-creatinine ratio (ACR) were associated with mortality. Models were adjusted for demographic, socioeconomic, behavioral, and clinical factors. Mean age in the population was 46 years, with 51.3% female, and 30.3% with an ACR ≥10 mg/g. Over a median follow-up of 9.5 years, 6813 deaths occurred. Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 132% overall (95% CI, 2.01-2.68), 124% among men (95% CI, 1.84-2.73), 158% among women (95% CI, 2.14-3.11), 130% among non-Hispanic White adults (95% CI: 1.89-2.79), 135% among non-Hispanic Black adults (95% CI, 1.82-3.04), and 114% among Hispanic adults (95% CI, 1.55-2.94). Compared with ACR <10, ACR ≥300 was associated with increased risk of mortality by 148% among individuals with neither hypertension nor hypercholesterolemia (95% CI, 1.69-3.64), 128% among individuals with hypertension alone (95% CI, 1.86-2.79), and 166% among individuals with both hypertension and hypercholesterolemia (95% CI, 2.18-3.26). Conclusions We found strong associations between albuminuria and mortality risk, even at mildly increased levels of albuminuria. Associations persisted across categories of sex, race or ethnicity, and comorbid conditions, with subtle differences.

Study of the Scattering Effect by SiO2 Nanoparticles, in a Luminescent Solar Concentrator Sensitized with Carbon Dots.

Luminescent solar concentrators (LSCs) have become an attractive way to produce green energy via their integration into buildings as photovoltaic windows. Recently, carbon quantum dots (C-QDs) have become the most studied luminescent material for the manufacture of luminescent solar concentrators due to their advantages, such as low toxicity, sustainability, and low cost. Despite the advantages of carbon quantum dots, they remain a low-efficiency material, and it is difficult to fabricate LSCs with a good performance. To address this problem, some of the research has used SiO2 nanoparticles (Nps) to produce a light-scattering effect that helps to improve the system performance. However, these studies are limited and have not been discussed in detail. In this regard, this research work was designed to evaluate the contribution of the scattering effect in different systems of carbon quantum dots used in a possible luminescent solar concentrator. To carry out this study, C-QDs and SiO2 Nps were synthesized by hydrothermal methods and the Stober method, respectively. We used different concentrations of both materials to fabricate film LSCs (10 × 10 cm2). The results show that the light scattered by the SiO2 Nps has a double contribution, in terms of light redirected towards the edges of the window and as a secondary source of excitation for the C-QDs; thus, an improvement in the performance of the LSC is achieved. The best improvement in photoluminescence is achieved when the films are composed of 20% wt carbon quantum dots and 10% wt SiO2 Nps, reaching a gain of 16% of the intensity of the light incident on the edges of the window with respect to the LSCs where only C-QDs were used.

Blood Pressure and Cardiovascular Disease Mortality Among US Adults: A Sex-Stratified Analysis, 1999-2019.

BACKGROUND: Most research examining the association between blood pressure (BP) and cardiovascular disease (CVD) is sex-agnostic. Our goal was to assess sex-specific associations between BP and CVD mortality. METHODS: We combined ten cycles of the National Health and Nutrition Examination Survey (1999-2018), N=53 289. Blood pressure was measured 3× and averaged. Data were linked to National Death Index data, and CVD mortality through December 31, 2019, was defined from International Classification of Diseases, Tenth Revision codes. We estimated sex-stratified, multivariable-adjusted incidence rate ratios (IRRs) for CVD mortality. RESULTS: Over a median follow-up of 9.5 years, there were 2405 CVD deaths. Associations between categories of systolic blood pressure (SBP) and diastolic blood pressure (DBP) with CVD mortality differed by sex (P<0.01). Among men, compared with SBP of 100 to <110 mm Hg, CVD mortality was 76% higher with SBP ≥160 mm Hg (IRR, 1.76 [95% CI, 1.27-2.44]). Among women, compared with SBP 100 to < 110 mm Hg, CVD mortality was 61% higher with SBP 130 to 139 mm Hg (IRR, 1.61 [95% CI, 1.02-2.55]), 75% higher with SBP 140 to 159 mm Hg (IRR, 1.75 [95% CI, 1.09-2.80]), and 113% higher with SBP≥160 mm Hg (IRR, 2.13 [95% CI, 1.35-3.36]). Compared with DBP 70 to <80 mm Hg, CVD mortality was higher with DBP <70 mm Hg and DBP≥80 mm Hg among men, and higher with DBP <50 mm Hg and DBP≥80 mm Hg among women. CONCLUSIONS: The association between BP and CVD mortality differed by sex, with increased CVD mortality risk present at lower levels of systolic blood pressure among women compared with men.

Identification of Glomerular and Plasma Apolipoprotein M as Novel Biomarkers in Glomerular Disease.

Introduction: Dysregulation of sphingolipid and cholesterol metabolism contributes to the pathogenesis of glomerular diseases (GDs). Apolipoprotein M (ApoM) promotes cholesterol efflux and modulates the bioactive sphingolipid sphingosine-1-phosphate (S1P). Glomerular ApoM expression is decreased in patients with focal segmental glomerulosclerosis (FSGS). We hypothesized that glomerular ApoM deficiency occurs in GD and that ApoM expression and plasma ApoM correlate with outcomes. Methods: Patients with GD from the Nephrotic Syndrome Study Network (NEPTUNE) were studied. We compared glomerular mRNA expression of ApoM (gApoM), sphingosine kinase 1 (SPHK1), and S1P receptors 1 to 5 (S1PR1-5) in patients (n = 84) and controls (n = 6). We used correlation analyses to determine associations between gApoM, baseline plasma ApoM (pApoM), and urine ApoM (uApoM/Cr). We used linear regression to determine whether gApoM, pApoM, and uApoM/Cr were associated with baseline estimated glomerular filtration rate (eGFR) and proteinuria. Using Cox models, we determined whether gApoM, pApoM, and uApoM/Cr were associated with complete remission (CR) and the composite of end-stage kidney disease (ESKD) or ≥40% eGFR decline. Results: gApoM was reduced (P < 0.01) and SPHK1 and S1PR1 to 5 expression was increased (P < 0.05) in patients versus controls, consistent with ApoM/S1P pathway modulation. gApoM positively correlated with pApoM in the overall cohort (r = 0.34, P < 0.01) and in the FSGS (r = 0.48, P < 0.05) and minimal change disease (MCD) (r = 0.75, P < 0.05) subgroups. Every unit decrease in gApoM and pApoM (log2) was associated with a 9.77 ml/min per 1.73 m2 (95% confidence interval [CI]: 3.96-15.57) and 13.26 ml/min per 1.73 m2 (95% CI: 3.57-22.96) lower baseline eGFR, respectively (P < 0.01). From Cox models adjusted for age, sex, or race, pApoM was a significant predictor of CR (hazard ratio [HR]: 1.85; 95% CI: 1.06-3.23). Conclusions: pApoM is a potential noninvasive biomarker of gApoM deficiency and strongly associates with clinical outcomes in GD.

One-year all-cause mortality in hospitalized patients with COVID-19 and end-stage renal disease undergoing hemodialysis.

INTRODUCTION: Patients with end-stage renal disease (ESRD) on dialysis and COVID-19 infection have an increased risk of in-hospital mortality, but whether these patients have a higher long-term mortality risk is unknown. MATERIALS AND METHODS: Retrospective chart review of 958 patients admitted with COVID-19 infection or those with ESRD admitted for any other reason between February 2020 and August 2020. We collected data on demographics, comorbidities, laboratory tests, and mortality. The primary outcome was all-cause 1-year mortality. The secondary outcome was in-hospital mortality. We used primarily logistic regression models to assess the mortality risk. RESULTS: In total, 651 patients without ESRD with COVID-19 (COVID+ESRD-), 259 with ESRD without COVID-19 (ESRD+COVID-), and 48 with ESRD with COVID-19 (COVID+ESRD+) were hospitalized between February 2020 and August 2020. Patients were followed after discharge until September 2021. The all-cause 1-year mortality rates were 24% in patients with COVID+ESRD-, 22% in ESRD+COVID- patients, and 40% in those with COVID+ESRD+ (p < 0.05). Compared to the COVID+ESRD- group, the unadjusted and adjusted odds ratio (OR) for all-cause 1-year mortality in the COVID+ESRD+ group was 2.13 (95% confidence interval (CI), 1.16 - 3.91) and 2.15 (95% CI,1.12 - 4.14), respectively. The unadjusted and adjusted OR for all-cause in-hospital mortality in the COVID+ESRD+ group was 1.79 (95% CI, 0.92 - 3.49); and 1.79 (95% CI, 0.88 - 3.65), respectively. We found no statistically significant difference between the COVID+ESRD- and ESRD+COVID- groups for both in-hospital and 1-year mortality (p > 0.05). CONCLUSION: Patients with COVID+ESRD+ have significantly higher odds for all-cause 1-year mortality compared to COVID+ESRD- patients. Future studies should investigate the mechanisms of long-term mortality risk in ESRD patients with COVID-19 infection.

Food protein-induced enterocolitis syndrome with pneumatosis intestinalis in an exclusively breastfed infant: A case report and literature review.

A 1-month-old male, exclusively breastfed, presented with 24 h of bloody stools, vomiting, metabolic acidosis, and pneumatosis intestinalis. The patient was initially treated for necrotizing enterocolitis (NEC). However, after suspecting food protein-induced enterocolitis syndrome (FPIES), oral feeding was resumed using an exclusive elemental formula, and the biochemical and radiological findings were resolved.

A psycho-educational intervention programme for parents with SGA foetuses supported by an adaptive mHealth system: design, proof of concept and usability assessment.

BACKGROUND: Technology-based approaches during pregnancy can facilitate the self-reporting of emotional health issues and improve well-being. There is evidence to suggest that stress during pregnancy can affect the foetus and result in restricted growth and preterm birth. Although a number of mobile health (mHealth) approaches are designed to monitor pregnancy and provide information about a specific aspect, no proposal specifically addresses the interventions in parents at risk of having small-for-gestational-age (SGA) or premature babies. Very few studies, however, follow any design and usability guidelines which aim to ensure end-user satisfaction when using these systems. RESULTS: We have developed an interactive, adaptable mHealth system to support a psycho-educational intervention programme for parents with SGA foetuses. The relevant results include a metamodel to support the task of modelling current or new intervention programmes, an mHealth system model with runtime adaptation to changes in the programme, the design of a usable app (called VivEmbarazo) and an architectural design and prototype implementation. The developed mHealth system has also enabled us to conduct a proof of concept based on the use of the mHealth systems and this includes data analysis and assesses usability and acceptance. CONCLUSIONS: The proof of concept confirms that parents are satisfied and that they are enthusiastic about the mHealth-supported intervention programme. It helps to technically validate the results obtained in the other stages relating to the development of the solution. The data analysis resulting from the proof of concept confirms that the stress experienced by parents who followed the mHealth-supported intervention programme was significantly lower than among those who did not follow it. This implies an improvement in the emotional health not only of the parents but also of their child. In fact, the babies of couples who followed the mHealth-supported programme weigh more than the babies of couples under traditional care. In terms of user acceptance and usability, the analysis confirms that mothers place greater value on the app design, usefulness and ease of use and are generally more satisfied than their partners. Although these results are promising in comparison with more traditional and other more recent technology-based approaches.

Safety and Efficacy of Belimumab in Patients with Lupus Nephritis: Open-Label Extension of BLISS-LN Study.

BACKGROUND AND OBJECTIVES: In the BLISS-LN study, belimumab improved kidney outcomes in adult patients with active lupus nephritis. This 28-week open-label extension of BLISS-LN assessed belimumab's safety and efficacy. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Eligible patients completing BLISS-LN received monthly intravenous belimumab 10 mg/kg plus standard therapy. End points included safety, open-label week 28 primary efficacy renal response (urine protein-creatinine ratio [UPCR] ≤0.7, eGFR no more than 20% below open-label baseline value or ≥60 ml/min per 1.73 m2, no prohibited medications) and complete renal response (UPCR <0.5, eGFR no more than 10% below open-label baseline value or ≥90 ml/min per 1.73 m2, no prohibited medications), and UPCR and eGFR by visit. Responses were also analyzed post hoc using the double-blind phase criteria. RESULTS: Of 257 enrolled patients, 255 were treated (safety population: n=123 switched from placebo-to-belimumab; n=132 remained on belimumab); 245 (97%) patients completed the study. Adverse events and serious adverse events were experienced by 62% and 4% of placebo-to-belimumab patients, respectively, and by 70% and 8% of belimumab-to-belimumab patients, respectively. One death occurred in the placebo-to-belimumab group. From open-label baseline to week 28, increases occurred in the proportions of patients achieving primary efficacy renal response (placebo-to-belimumab: from 60% to 67%; belimumab-to-belimumab: from 70% to 75%) and complete renal response (placebo-to-belimumab: from 36% to 48%; belimumab-to-belimumab: from 48% to 62%). Based on double-blind phase criteria, changes also occurred in the proportions achieving primary efficacy renal response (placebo-to-belimumab: from 54% to 53%; belimumab-to-belimumab: from 66% to 52%) and complete renal response (placebo-to-belimumab: from 34% to 35%; belimumab-to-belimumab: from 46% to 41%). The seeming decrease in response rates in the belimumab-to-belimumab groups was attributed to discontinuations/administration of glucocorticoids for non-SLE reasons as opposed to nephritis. Median UPCR and eGFR values were similar at open-label baseline and week 28. CONCLUSIONS: No new safety signals were identified, and efficacy was generally maintained throughout the open-label phase. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: BLISS-LN, NCT01639339.

A secondary analysis of the Belimumab International Study in Lupus Nephritis trial examined effects of belimumab on kidney outcomes and preservation of kidney function in patients with lupus nephritis.

We performed a post hoc analysis of the Belimumab International Study in Lupus Nephritis (BLISS-LN), a Phase 3, multinational, double-blind, 104-week trial, in which 448 patients with lupus nephritis were randomized to receive intravenous belimumab 10 mg/kg or placebo with standard therapy (cyclophosphamide/azathioprine or mycophenolate mofetil). Add-on belimumab was found to be most effective in improving the primary efficacy kidney response and complete kidney response in patients with proliferative lupus nephritis and a baseline urine protein/creatinine ratio under 3 g/g. However, there was no observed improvement in the kidney response with belimumab treatment in patients with lupus nephritis and sub-epithelial deposits or with a baseline protein/creatinine ratio of 3 g/g or more. Belimumab significantly reduced the risk of kidney-related events or death and lupus nephritis flare in the overall population. Belimumab reduced the risk of a sustained 30% or 40% decline in estimated glomerular filtration rate (eGFR) versus standard treatment alone and attenuated the annual rate of eGFR decline in patients who remained on-study. Thus, our data suggest that the addition of belimumab to standard therapy could attenuate the risk of lupus nephritis flare and eGFR decline in a broad spectrum of patients with lupus nephritis.

Discoidin domain receptor 1 activation links extracellular matrix to podocyte lipotoxicity in Alport syndrome.

BACKGROUND: Discoidin domain receptor 1 (DDR1) is a receptor tyrosine kinase that is activated by collagens that is involved in the pathogenesis of fibrotic disorders. Interestingly, de novo production of the collagen type I (Col I) has been observed in Col4a3 knockout mice, a mouse model of Alport Syndrome (AS mice). Deletion of the DDR1 in AS mice was shown to improve survival and renal function. However, the mechanisms driving DDR1-dependent fibrosis remain largely unknown. METHODS: Podocyte pDDR1 levels, Collagen and cluster of differentiation 36 (CD36) expression was analyzed by Real-time PCR and Western blot. Lipid droplet accumulation and content was determined using Bodipy staining and enzymatic analysis. CD36 and DDR1 interaction was determined by co-immunoprecipitation. Creatinine, BUN, albuminuria, lipid content, and histological and morphological assessment of kidneys harvested from AS mice treated with Ezetimibe and/or Ramipril or vehicle was performed. FINDINGS: We demonstrate that Col I-mediated DDR1 activation induces CD36-mediated podocyte lipotoxic injury. We show that Ezetimibe interferes with the CD36/DDR1 interaction in vitro and prevents lipotoxicity in AS mice thus preserving renal function similarly to ramipril. INTERPRETATION: Our study suggests that Col I/DDR1-mediated lipotoxicity contributes to renal failure in AS and that targeting this pathway may represent a new therapeutic strategy for patients with AS and with chronic kidney diseases (CKD) associated with Col4 mutations. FUNDING: This study is supported by the NIH grants R01DK117599, R01DK104753, R01CA227493, U54DK083912, UM1DK100846, U01DK116101, UL1TR000460 (Miami Clinical Translational Science Institute, National Center for Advancing Translational Sciences and the National Institute on Minority Health and Health Disparities), F32DK115109, Hoffmann-La Roche and Alport Syndrome Foundation.

A Multicenter Randomized Clinical Trial of Hemodialysis Access Blood Flow Surveillance Compared to Standard of Care: The Hemodialysis Access Surveillance Evaluation (HASE) Study.

INTRODUCTION: Arteriovenous (AV) access thrombosis remains 1 of the most troubling AV access-related complications affecting hemodialysis patients. It necessitates an urgent and occasionally complicated thrombectomy procedure and increases the risk of AV access loss. AV access stenosis is found in the majority of thrombosed AV accesses. The routine use of AV access surveillance for the early detection and management of stenosis to reduce the thrombosis rate remains controversial. METHODS: We have conducted a multicenter, prospective, randomized clinical trial comparing the standard of care coupled with ultrasound dilution technique (UDT) flow measurement monthly surveillance with the standard of care alone. RESULTS: We prospectively randomized 436 patients with end-stage renal disease on hemodialysis with arteriovenous fistula (AVF) or arteriovenous graft (AVG) using cluster (shift) randomization to surveillance and control groups. There were no significant differences in the baseline demographic data between the 2 groups, except for ethnicity (P = 0.017). Patients were followed on average for 15.2 months. There were significantly less per-patient thrombotic events (Poisson rate) in the surveillance group (0.12/patient) compared with the control group (0.23/patient) (P = 0.012). There was no statistically significant difference in the total number of procedures between the 2 groups, irrespective of whether thrombectomy procedures were included or excluded, and no statistically significant differences in the rate of or time to the first thrombotic event or the number of catheters placed due to thrombosis. CONCLUSION: The use of UDT flow measurement monthly AV access surveillance in this multicenter randomized controlled trial reduced the per-patient thrombotic events without significantly increasing the total number of angiographic procedures. Even though there is a trend, surveillance did not reduce the first thrombotic event rate.

Hypofractionated radiation therapy for early breast cancer: Follow up of a new treatment standard.

AIM: To assess the oncological outcomes of patients with early breast cancer treated with breast-conserving surgery and adjuvant hypofractionated radiation therapy. METHODS AND MATERIAL: This retrospective analysis included all patients ≥50 year of age with T1-2 N0 M0 breast cancer treated at our Radiation Oncology Unit between 2008 and 2011. Whole-breast radiation therapy was delivered to a dose of 42.5 Gy in 16 fractions, without boost. The primary outcome was local control. RESULTS: 212 patients were identified. With a median follow up of 60 months, we found 3% local recurrence and 5.3% regional and/or distant recurrences. At the moment of data analysis, 17 patients had died. Out of 5 local recurrences, 2 had previously had a distant recurrence, both of them died. The other three were still alive at the last follow up. These results are comparable to those observed in Phase III trials that use this fractionation scheme. CONCLUSIONS: The results obtained with this retrospective analysis are comparable to those obtained in large randomized trials. This data also supports the use of hypofractionated radiation therapy in Latin America. Hypofractionated radiation therapy for early breast cancer patients should be the standard adjuvant treatment.

Two-Year, Randomized, Controlled Trial of Belimumab in Lupus Nephritis.

BACKGROUND: In adults with active lupus nephritis, the efficacy and safety of intravenous belimumab as compared with placebo, when added to standard therapy (mycophenolate mofetil or cyclophosphamide-azathioprine), are unknown. METHODS: In a phase 3, multinational, multicenter, randomized, double-blind, placebo-controlled, 104-week trial conducted at 107 sites in 21 countries, we assigned adults with biopsy-proven, active lupus nephritis in a 1:1 ratio to receive intravenous belimumab (at a dose of 10 mg per kilogram of body weight) or matching placebo, in addition to standard therapy. The primary end point at week 104 was a primary efficacy renal response (a ratio of urinary protein to creatinine of ≤0.7, an estimated glomerular filtration rate [eGFR] that was no worse than 20% below the value before the renal flare (pre-flare value) or ≥60 ml per minute per 1.73 m2 of body-surface area, and no use of rescue therapy), and the major secondary end point was a complete renal response (a ratio of urinary protein to creatinine of <0.5, an eGFR that was no worse than 10% below the pre-flare value or ≥90 ml per minute per 1.73 m2, and no use of rescue therapy). The time to a renal-related event or death was assessed. RESULTS: A total of 448 patients underwent randomization (224 to the belimumab group and 224 to the placebo group). At week 104, significantly more patients in the belimumab group than in the placebo group had a primary efficacy renal response (43% vs. 32%; odds ratio, 1.6; 95% confidence interval [CI], 1.0 to 2.3; P = 0.03) and a complete renal response (30% vs. 20%; odds ratio, 1.7; 95% CI, 1.1 to 2.7; P = 0.02). The risk of a renal-related event or death was lower among patients who received belimumab than among those who received placebo (hazard ratio, 0.51; 95% CI, 0.34 to 0.77; P = 0.001). The safety profile of belimumab was consistent with that in previous trials. CONCLUSIONS: In this trial involving patients with active lupus nephritis, more patients who received belimumab plus standard therapy had a primary efficacy renal response than those who received standard therapy alone. (Funded by GlaxoSmithKline; BLISS-LN ClinicalTrials.gov number, NCT01639339.).

Sterol-O-acyltransferase-1 has a role in kidney disease associated with diabetes and Alport syndrome.

Defective cholesterol metabolism primarily linked to reduced ATP-binding cassette transporter A1 (ABCA1) expression is closely associated with the pathogenesis and progression of kidney diseases, including diabetic kidney disease and Alport Syndrome. However, whether the accumulation of free or esterified cholesterol contributes to progression in kidney disease remains unclear. Here, we demonstrate that inhibition of sterol-O-acyltransferase-1 (SOAT1), the enzyme at the endoplasmic reticulum that converts free cholesterol to cholesterol esters, which are then stored in lipid droplets, effectively reduced cholesterol ester and lipid droplet formation in human podocytes. Furthermore, we found that inhibition of SOAT1 in podocytes reduced lipotoxicity-mediated podocyte injury in diabetic kidney disease and Alport Syndrome in association with increased ABCA1 expression and ABCA1-mediated cholesterol efflux. In vivo, Soat1 deficient mice did not develop albuminuria or mesangial expansion at 10-12 months of age. However, Soat1 deficiency/inhibition in experimental models of diabetic kidney disease and Alport Syndrome reduced cholesterol ester content in kidney cortices and protected from disease progression. Thus, targeting SOAT1-mediated cholesterol metabolism may represent a new therapeutic strategy to treat kidney disease in patients with diabetic kidney disease and Alport Syndrome, like that suggested for Alzheimer's disease and cancer treatments.

Outcomes in adults with systolic blood pressure between 130 and 139 mmHg in Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial and Systolic Blood Pressure Intervention Trial.

BACKGROUND: Patients with stage 1 systolic hypertension have increased risk of cardiovascular disease (CVD) events. METHODS: Using Cox models, we assess the effect of targeting an intensive SBP goal of less than 120 mmHg compared with standard SBP goal of less than 140 mmHg on the risk of CVD events in adults with stage 1 systolic hypertension with diabetes mellitus enrolled in Action to Control Cardiovascular Risk in Diabetes Blood Pressure trial (ACCORD BP) (n = 1901) and without diabetes mellitus enrolled in Systolic Blood Pressure Intervention Trial (SPRINT) (n = 3484) that used identical SBP goal interventions. OUTCOMES: In ACCORD BP, the primary composite CVD outcome was the first occurrence of myocardial infarction, stroke, or CVD mortality. In SPRINT, the primary composite CVD outcome was the first occurrence of myocardial infarction, other acute coronary syndrome, stroke, heart failure, or CVD mortality. RESULTS: In SPRINT, targeting an intensive SBP goal significantly reduced the risk of the primary CVD outcome [hazard ratio 0.75 (95% confidence interval, 0.58-0.98); events 1.78 vs. 2.37%/year]. In ACCORD BP, the relationships of SBP goal with the primary CVD outcome was modified by the glycemia goal intervention (interaction P = 0.039). In the standard glycemia subgroup (A1c target 7-7.9%), intensive SBP goal significantly reduced the risk of the primary CVD outcome [hazard ratio 0.61 (0.40-0.94); events 1.63 vs. 2.56%/year]. In the intensive glycemia subgroup (A1c target <6%), the risk of the primary CVD outcome was not significantly different between groups [hazard ratio 1.20 (0.76-1.89); events 1.91 vs. 1.60%/year]. CONCLUSION: Targeting an intensive SBP goal significantly reduced the risk of CVD events in patients with stage 1 systolic hypertension without diabetes and with diabetes on standard glycemia goal.