Sodium-glucose cotransporter 2 inhibition in primary and secondary glomerulonephritis.

BACKGROUND: The role of sodium-glucose cotransporter 2 inhibitors (SGLT2i) in the management glomerular/systemic autoimmune diseases with proteinuria in real-world clinical settings is unclear. METHODS: This is a retrospective, observational, international cohort study. Adult patients with biopsy-proven glomerular diseases were included. The main outcome was the percentage reduction in 24-h proteinuria from SGLT2i initiation to 3, 6, 9 and 12 months. Secondary outcomes included percentage change in estimated glomerular filtration rate (eGFR), proteinuria reduction by type of disease and reduction of proteinuria ≥30% from SGLT2i initiation. RESULTS: Four-hundred and ninety-three patients with a median age of 55 years and background therapy with renin-angiotensin system blockers were included. Proteinuria from baseline changed by -35%, -41%, -45% and -48% at 3, 6, 9 and 12 months after SGLT2i initiation, while eGFR changed by -6%, -3%, -8% and -10.5% at 3, 6, 9 and 12 months, respectively. Results were similar irrespective of the underlying disease. A correlation was found between body mass index (BMI) and percentage proteinuria reduction at last follow-up. By mixed-effects logistic regression model, serum albumin at SGLT2i initiation emerged as a predictor of ≥30% proteinuria reduction (odds ratio for albumin <3.5 g/dL, 0.53; 95% CI 0.30-0.91; P = .02). A slower eGFR decline was observed in patients achieving a ≥30% proteinuria reduction: -3.7 versus -5.3 mL/min/1.73 m2/year (P = .001). The overall tolerance to SGLT2i was good. CONCLUSIONS: The use of SGLT2i was associated with a significant reduction of proteinuria. This percentage change is greater in patients with higher BMI. Higher serum albumin at SGLT2i onset is associated with higher probability of achieving a ≥30% proteinuria reduction.

Recovery of dialysis patients with COVID-19: health outcomes 3 months after diagnosis in ERACODA.

BACKGROUND: Coronavirus disease 2019 (COVID-19)-related short-term mortality is high in dialysis patients, but longer-term outcomes are largely unknown. We therefore assessed patient recovery in a large cohort of dialysis patients 3 months after their COVID-19 diagnosis. METHODS: We analyzed data on dialysis patients diagnosed with COVID-19 from 1 February 2020 to 31 March 2021 from the European Renal Association COVID-19 Database (ERACODA). The outcomes studied were patient survival, residence and functional and mental health status (estimated by their treating physician) 3 months after COVID-19 diagnosis. Complete follow-up data were available for 854 surviving patients. Patient characteristics associated with recovery were analyzed using logistic regression. RESULTS: In 2449 hemodialysis patients (mean ± SD age 67.5 ± 14.4 years, 62% male), survival probabilities at 3 months after COVID-19 diagnosis were 90% for nonhospitalized patients (n = 1087), 73% for patients admitted to the hospital but not to an intensive care unit (ICU) (n = 1165) and 40% for those admitted to an ICU (n = 197). Patient survival hardly decreased between 28 days and 3 months after COVID-19 diagnosis. At 3 months, 87% functioned at their pre-existent functional and 94% at their pre-existent mental level. Only few of the surviving patients were still admitted to the hospital (0.8-6.3%) or a nursing home (∼5%). A higher age and frailty score at presentation and ICU admission were associated with worse functional outcome. CONCLUSIONS: Mortality between 28 days and 3 months after COVID-19 diagnosis was low and the majority of patients who survived COVID-19 recovered to their pre-existent functional and mental health level at 3 months after diagnosis.

Cardiovascular risk factors and the impact on prognosis in patients with chronic kidney disease secondary to autosomal dominant polycystic kidney disease.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is the most frequent hereditary renal disease. There is an increased rate of cardiovascular disease (CVD) in ADPKD. In this study, we evaluate the prevalence of cardiovascular risk factors, the achievement rates for treatment goals and cardiovascular events (CVE) in ADPKD and their relations with asymptomatic CVD in CKD from other etiologies (CKDoe) and controls. METHODS: We evaluated 2445 CKD patients (2010-2012). The information collected was: clinical, anthropometric and analytical parameters, treatments and CVD evaluation (intima-media thickness (IMT), atheromatous plaque presence and ankle-brachial index (ABI)). Laboratory, vital status, CVE and hospitalizations were collected for 4 years. RESULTS: ADPKD patients had a worse renal function and worst achievement of blood pressure, higher parathormone levels but lower proteinuria compared to CKDoe. ADPKD patients presented lower IMT values than other groups, however, an intermediate rate of pathologic ABI and atheromatous plaque was present. More than half of the patients received statins, achieving LDL-c levels < 100 only in 50 and 39.8% of them (ADPKD and CKDoe respectively). The number of CVE during the follow-up period was low. In adjusted Cox regression model, ADPDK had the lowest occurrence of CVE of all three groups (HR:0.422, 95%CI 0.221-0.808, p = 0.009). CONCLUSION: ADPKD patients show intermediate control rates of CVD. A better control of CVD risk seems to be related with a lower load of CVD compared to other groups, which may lead in the long term to a better prognosis. Further investigation is necessary to determine cardiovascular prognosis in ADPKD.

A Compression-Based Method for Detecting Anomalies in Textual Data.

Nowadays, information and communications technology systems are fundamental assets of our social and economical model, and thus they should be properly protected against the malicious activity of cybercriminals. Defence mechanisms are generally articulated around tools that trace and store information in several ways, the simplest one being the generation of plain text files coined as security logs. Such log files are usually inspected, in a semi-automatic way, by security analysts to detect events that may affect system integrity, confidentiality and availability. On this basis, we propose a parameter-free method to detect security incidents from structured text regardless its nature. We use the Normalized Compression Distance to obtain a set of features that can be used by a Support Vector Machine to classify events from a heterogeneous cybersecurity environment. In particular, we explore and validate the application of our method in four different cybersecurity domains: HTTP anomaly identification, spam detection, Domain Generation Algorithms tracking and sentiment analysis. The results obtained show the validity and flexibility of our approach in different security scenarios with a low configuration burden.

COVID-19: clinical course and outcomes of 36 hemodialysis patients in Spain.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia emerged in Wuhan, China in December 2019. Unfortunately, there is a lack of evidence about the optimal management of novel coronavirus disease 2019 (COVID-19), and even less is available in patients on maintenance hemodialysis therapy than in the general population. In this retrospective, observational, single-center study, we analyzed the clinical course and outcomes of all maintenance hemodialysis patients hospitalized with COVID-19 from March 12th to April 10th, 2020 as confirmed by real-time polymerase chain reaction. Baseline features, clinical course, laboratory data, and different therapies were compared between survivors and nonsurvivors to identify risk factors associated with mortality. Among the 36 patients, 11 (30.5%) died, and 7 were able to be discharged within the observation period. Clinical and radiological evolution during the first week of admission were predictive of mortality. Among the 36 patients, 18 had worsening of their clinical status, as defined by severe hypoxia with oxygen therapy requirements greater than 4 L/min and radiological worsening. Significantly, 11 of those 18 patients (61.1%) died. None of the classical cardiovascular risk factors in the general population were associated with higher mortality. Compared to survivors, nonsurvivors had significantly longer dialysis vintage, increased lactate dehydrogenase (490 U/l ± 120 U/l vs. 281 U/l ± 151 U/l, P = 0.008) and C-reactive protein levels (18.3 mg/dl ± 13.7 mg/dl vs. 8.1 mg/dl ± 8.1 mg/dl, P = 0.021), and a lower lymphocyte count (0.38 ×103/µl ± 0.14 ×103/µl vs. 0.76 ×103/µl ± 0.48 ×103/µl, P = 0.04) 1 week after clinical onset. Thus, the mortality among hospitalized hemodialysis patients diagnosed with COVID-19 is high. Certain laboratory tests can be used to predict a worsening clinical course.

COVID-19-related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration.

BACKGROUND: Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. METHODS: We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. RESULTS: Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3-30.2%] in kidney transplant and 25.0% (95% CI 20.2-30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59-1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation <1 year before presentation (HR adjusted for sex, age and frailty 0.20, 95% CI 0.07-0.56, P < 0.01). CONCLUSIONS: The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.

Autosomal Dominant Tubulointerstitial Kidney Disease: Clinical Presentation of Patients With ADTKD-UMOD and ADTKD-MUC1.

RATIONALE & OBJECTIVE: Autosomal dominant tubulointerstitial kidney disease (ADTKD) is a rare underdiagnosed cause of end-stage renal disease (ESRD). ADTKD is caused by mutations in at least 4 different genes: MUC1, UMOD, HNF1B, and REN. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 56 families (131 affected individuals) with ADTKD referred from different Spanish hospitals. Clinical, laboratory, radiologic, and pathologic data were collected, and genetic testing for UMOD, MUC1, REN, and HNF1B was performed. PREDICTORS: Hyperuricemia, ultrasound findings, renal histology, genetic mutations. OUTCOMES: Age at ESRD, rate of decline in estimated glomerular filtration rate. RESULTS: ADTKD was diagnosed in 25 families (45%), 9 carried UMOD pathogenic variants (41 affected members), and 16 carried the MUC1 pathogenic mutation c.(428)dupC (90 affected members). No pathogenic variants were identified in REN or HNF1B. Among the 77 individuals who developed ESRD, median age at onset of ESRD was 51 years for those with ADTKD-MUC1 versus 56 years (P=0.1) for those with ADTKD-UMOD. Individuals with the MUC1 duplication presented higher risk for developing ESRD (HR, 2.24; P=0.03). The slope of decline in estimated glomerular filtration rate showed no significant difference between groups (-3.0mL/min/1.73m2 per year in the ADTKD-UMOD group versus -3.9mL/min/1.73m2 per year in the ADTKD-MUC1 group; P=0.2). The prevalence of hyperuricemia was significantly higher in individuals with ADTKD-UMOD (87% vs 54%; P=0.006). Although gout occurred more frequently in this group, the difference was not statistically significant (24% vs 7%; P=0.07). LIMITATIONS: Relatively small Spanish cohort. MUC1 analysis limited to cytosine duplication. CONCLUSIONS: The main genetic cause of ADTKD in our Spanish cohort is the MUC1 pathogenic mutation c.(428)dupC. Renal survival may be worse in individuals with the MUC1 mutation than in those with UMOD mutations. Clinical presentation does not permit distinguishing between these variants. However, hyperuricemia and gout are more frequent in individuals with ADTKD-UMOD.

Stratifying risk in the prevention of recurrent variceal hemorrhage: Results of an individual patient meta-analysis.

Endoscopic variceal ligation plus beta-blockers (EVL+BB) is currently recommended for variceal rebleeding prophylaxis, a recommendation that extends to all patients with cirrhosis with previous variceal bleeding irrespective of prognostic stage. Individualizing patient care is relevant, and in published studies on variceal rebleeding prophylaxis, there is a lack of information regarding response to therapy by prognostic stage. This study aimed at comparing EVL plus BB with monotherapy (EVL or BB) on all-source rebleeding and mortality in patients with cirrhosis and previous variceal bleeding stratified by cirrhosis severity (Child A versus B/C) by means of individual time-to-event patient data meta-analysis from randomized controlled trials. The study used individual data on 389 patients from three trials comparing EVL plus BB versus BB and 416 patients from four trials comparing EVL plus BB versus EVL. Compared with BB alone, EVL plus BB reduced overall rebleeding in Child A (incidence rate ratio 0.40; 95% confidence interval, 0.18-0.89; P = 0.025) but not in Child B/C, without differences in mortality. The effect of EVL on rebleeding was different according to Child (P for interaction <0.001). Conversely, compared with EVL, EVL plus BB reduced rebleeding in both Child A and B/C, with a significant reduction in mortality in Child B/C (incidence rate ratio 0.46; 95% confidence interval, 0.25-0.85; P = 0.013). CONCLUSION: Outcomes of therapies to prevent variceal rebleeding differ depending on cirrhosis severity: in patients with preserved liver function (Child A), combination therapy is recommended because it is more effective in preventing rebleeding, without modifying survival, while in patients with advanced liver failure (Child B/C), EVL alone carries an increased risk of rebleeding and death compared with combination therapy, underlining that BB is the key element of combination therapy. (Hepatology 2017;66:1219-1231).

Aspirin for Primary Prevention of Cardiovascular Disease and Renal Disease Progression in Chronic Kidney Disease Patients: a Multicenter Randomized Clinical Trial (AASER Study).

BACKGROUND: Patients with chronic kidney disease (CKD) are at high risk for developing cardiovascular events. However, limited evidence is available regarding the use of aspirin in CKD patients to decrease cardiovascular risk and to slow renal disease progression. STUDY DESIGN: Prospective, multicenter, open-label randomized controlled trial. SETTING AND PARTICIPANTS: One hundred eleven patients with estimated glomerular filtration rate (eGFR) 15-60 ml/min/1.73 m2 without previous cardiovascular events. INTERVENTION: Aspirin treatment (100 mg/day) (n = 50) or usual therapy (n = 61). Mean follow-up time was 64.8 ± 16.4 months. OUTCOMES: The primary endpoint was composed of cardiovascular death, acute coronary syndrome (nonfatal MI, coronary revascularization, or unstable angina pectoris), cerebrovascular disease, heart failure, or nonfatal peripheral arterial disease. Secondary endpoints were fatal and nonfatal coronary events, renal events (defined as doubling of serum creatinine, ≥ 50% decrease in eGFR, or renal replacement therapy), and bleeding episodes. RESULTS: During follow-up, 17 and 5 participants suffered from a primary endpoint in the control and aspirin groups, respectively. Aspirin did not significantly reduce primary composite endpoint (HR, 0.396 (0.146-1.076), p = 0.069. Eight patients suffered from a fatal or nonfatal coronary event in the control group compared to no patients in the aspirin group. Aspirin significantly reduced the risk of coronary events (log-rank, 5.997; p = 0.014). Seventeen patients in the control group reached the renal outcome in comparison with 3 patients in the aspirin group. Aspirin treatment decreased renal disease progression in a model adjusted for age, baseline kidney function, and diabetes mellitus (HR, 0.272; 95% CI, 0.077-0.955; p = 0.043) but did not when adjusted for albuminuria. No differences were found in minor bleeding episodes between groups and no major bleeding was registered. LIMITATIONS: Small sample size and open-label trial. CONCLUSIONS: Long-term treatment with low-dose aspirin did not reduce the composite primary endpoint; however, there were reductions in secondary endpoints with fewer coronary events and renal outcomes. ClinicalTrials.gov Identifier: NCT01709994.

Retinal Waves Modulate an Intraretinal Circuit of Intrinsically Photosensitive Retinal Ganglion Cells.

UNLABELLED: Before the maturation of rod and cone photoreceptors, the developing retina relies on light detection by intrinsically photosensitive retinal ganglion cells (ipRGCs) to drive early light-dependent behaviors. ipRGCs are output neurons of the retina; however, they also form functional microcircuits within the retina itself. Whether ipRGC microcircuits exist during development and whether they influence early light detection remain unknown. Here, we investigate the neural circuit that underlies the ipRGC-driven light response in developing mice. We use a combination of calcium imaging, tracer coupling, and electrophysiology experiments to show that ipRGCs form extensive gap junction networks that strongly contribute to the overall light response of the developing retina. Interestingly, we found that gap junction coupling was modulated by spontaneous retinal waves, such that acute blockade of waves dramatically increased the extent of coupling and hence increased the number of light-responsive neurons. Moreover, using an optical sensor, we found that this wave-dependent modulation of coupling is driven by dopamine that is phasically released by retinal waves. Our results demonstrate that ipRGCs form gap junction microcircuits during development that are modulated by retinal waves; these circuits determine the extent of the light response and thus potentially impact the processing of early visual information and light-dependent developmental functions. SIGNIFICANCE STATEMENT: Light-dependent functions in early development are mediated by intrinsically photosensitive retinal ganglion cells (ipRGCs). Here we show that ipRGCs form an extensive gap junction network with other retinal neurons, including other ipRGCs, which shapes the retina's overall light response. Blocking cholinergic retinal waves, which are the primary source of neural activity before maturation of photoreceptors, increased the extent of ipRGC gap junction networks, thus increasing the number of light-responsive cells. We determined that this modulation of ipRGC gap junction networks occurs via dopamine released by waves. These results demonstrate that retinal waves mediate dopaminergic modulation of gap junction networks to regulate pre-vision light responses.

Mineral metabolism factors predict accelerated progression of common carotid intima-media thickness in chronic kidney disease: the NEFRONA study.

BACKGROUND: The leading cause of premature death in chronic kidney disease (CKD) is cardiovascular disease (CVD), but risk assessment in renal patients is challenging. The aim of the study was to analyse the factors that predict accelerated progression of common carotid intima-media thickness (CCIMT) in a CKD cohort after 2 years of follow-up (2010-12). METHODS: The study included 1152 patients from the NEFRONA cohort with CKD stages 3-5D and without a clinical history of CVD. CCIMT was measured at the far wall on both common carotids. CCIMT progression was defined as the change between CCIMT at baseline and at 24 months for each side, averaged and normalized as change per year. Accelerated progressors were defined as those with a CCIMT change ≥75th percentile. RESULTS: The median CCIMT progression rate was 0.0125 mm/year, without significant differences between CKD stages. The cut-off value for defining accelerated progression was 0.0425 mm/year. After adjustment, age was a common factor among all CKD stages. Traditional cardiovascular risk factors, such as diabetes and systolic blood pressure, were predictors of progression in CKD stages 4-5, whereas high-density lipoprotein and low-density lipoprotein cholesterol predicted progression in women in stage 3. Mineral metabolism factors predicting accelerated progression were serum phosphorus in stages 3 and 5D; low 25-hydroxyvitamin D and parathyroid hormone levels >110 pg/mL in stages 4-5 and intact parathyroid hormone levels out of the recommended range in stage 5D. CONCLUSIONS: Mineral metabolism parameters might predict accelerated CCIMT progression from early CKD stages.

Factors influencing pathological ankle-brachial index values along the chronic kidney disease spectrum: the NEFRONA study.

Background: The ankle-brachial index (ABI) is widely used to diagnose subclinical peripheral artery disease (PAD) in the general population, but data assessing its prevalence and related factors in different chronic kidney disease (CKD) stages are scarce. The aim of this study is to evaluate the prevalence and associated factors of pathological ABI values in CKD patients. Methods: NEFRONA is a multicentre prospective project that included 2445 CKD patients from 81 centres and 559 non-CKD subjects from 9 primary care centres across Spain. A trained team collected clinical and laboratory data, performed vascular ultrasounds and measured the ABI. Results: PAD prevalence was higher in CKD than in controls (28.0 versus 12.3%, P < 0.001). Prevalence increased in more advanced CKD stages, due to more patients with an ABI ≥1.4, rather than ≤0.9. Diabetes was the only factor predicting both pathological values in all CKD stages. Age, female sex, carotid plaques, higher carotid intima-media thickness, higher high-sensitivity C-reactive protein (hsCRP) and triglycerides, and lower 25-hydroxi-vitamin D were independently associated with an ABI ≤0.9. Higher phosphate and hsCRP, lower low-density lipoprotein (LDL)-cholesterol and dialysis were associated with an ABI ≥1.4. A stratified analysis showed different associated factors in each CKD stage, with phosphate being especially important in earlier CKD, and LDL-cholesterol being an independent predictor only in Sage 5D CKD. Conclusions: Asymptomatic PAD is very prevalent in all CKD stages, but factors related to a low or high pathological ABI differ, revealing different pathogenic pathways. Diabetes, dyslipidaemia, inflammation and mineral-bone disorders play a role in the appearance of PAD in CKD.

Predictors of response and relapse in patients with idiopathic membranous nephropathy treated with tacrolimus.

BACKGROUND: Although tacrolimus is recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of idiopathic membranous nephropathy (MN), little is known about factors that influence response and relapse of the disease after tacrolimus therapy. METHODS: Multicentre study that collected 122 MN patients with nephrotic syndrome and stable renal function treated with tacrolimus. Duration of treatment was 17.6 ± 7.2 months, including a full-dose and a tapering period. RESULTS: The percentage of remission was 60, 78 and 84% after 6, 12 and 18 months of treatment, respectively. The amount of proteinuria at baseline significantly predicted remission, the lower the baseline proteinuria the higher the probability of remission. Only 10 patients (8%) received concomitantly corticosteroids, and their rate of remission was similar (80% at 18 months). Among responders, 42% achieved complete remission (CR) and 58% partial remission (PR). Almost half (44%) of the responder patients relapsed. The amount of proteinuria at the onset of tacrolimus tapering was significantly higher in relapsing patients. By multivariable analysis, the presence of a PR versus CR at the onset of tacrolimus tapering and a shorter duration of the tapering period significantly predicted relapses. Tolerance was good and the number of adverse events low. CONCLUSIONS: Tacrolimus monotherapy is an effective and safe option for the treatment of MN with stable renal function. Relapses are frequent in patients with PR and can be partially prevented by a longer tapering period.

Observational multicenter study to evaluate the prevalence and prognosis of subclinical atheromatosis in a Spanish chronic kidney disease cohort: baseline data from the NEFRONA study.

BACKGROUND: Cardiovascular events (CVE) are more prevalent in chronic kidney disease (CKD) than in general population, being the main cause of morbimortality. Specific risk factors related to CKD have been suggested, because traditional factors do not fully explain this increase in cardiovascular disease rates. However, the role of atheromatosis, its pathogenesis and evolution are still unclear. The potential use of diagnostic tests to detect subclinical atheromatosis has to be determined. METHODS: NEFRONA is a prospective multicenter cohort study. 2445 CKD subjects were enrolled from 81 Spanish hospitals and dialysis clinics, from 2010 to 2012. Eligibility criteria included: 18 to 74 years old, CKD stage 3 or higher, and no previous CVE. 559 non-CKD controls were also recruited. Demographical, clinical and analytical data were collected. Carotid and femoral ultrasounds were performed by a single trained team to measure carotid intima-media thickness (cIMT) and detect atheromatous plaques. Ankle-brachial index (ABI) was measured. RESULTS: Differences in age, sex and prevalence and control of cardiovascular risk factors were found between controls and CKD patients. These differences are similar to those described in epidemiological studies.No difference was found regarding cIMT between controls and CKD (when subjects with plaques in common carotid arteries were omitted); earlier CKD stages had higher values. CKD patients had a higher rate of atheromatous plaques, with no difference between stages in the unadjusted analysis. A group of patients had plaques in femoral arteries but were plaque-free in carotid arteries, and would have gone underdiagnosed without the femoral study. The percentage of pathologic ABI was higher in CKD, with higher prevalence in more advanced stages, and a higher rate of ABI >1.4 than <0.9, suggesting more vascular calcification. CONCLUSIONS: NEFRONA is the first large study describing the actual prevalence of subclinical atheromatosis across different CKD stages. There is a very high rate of atheromatous plaques and pathologic ABI in CKD. Prospective data will add important information to the pathogenesis and evolution of atheromatosis in CKD, compared to non-CKD subjects.

Tubular biomarkers and histology in lupus nephritis.

INTRODUCTION: The relevance of tubulo-interstitial involvement for kidney prognosis has recently been emphasized, but validated biomarkers for predicting histology are still lacking. The aim of our study was to evaluate different serum and urinary markers of tubular damage in patients with lupus nephritis (LN) and to correlate them with kidney histopathology. METHODS: A single-center retrospective study was conducted from January 2016 to December 2021. Serum and urine samples were collected on the same day of kidney biopsy and correlated with histologic data from a cohort of 15 LN patients. We analyzed the following urinary markers, adjusted for urine creatinine: beta 2-microglobulin, alpha 1-microglobulin, NGAL, uKIM-1, MCP-1, uDKK-3, and uUMOD. The serum markers sKIM-1 and sUMOD were also analyzed. RESULTS: A positive and strong correlation was observed between the degree of interstitial fibrosis (rho = 0.785, p = .001) and tubular atrophy (rho = 0.781, p = .001) and the levels of uDKK3. uUMOD also showed an inverse and moderate correlation with interstitial fibrosis (rho = -0.562, p = .037) and tubular atrophy (rho = -0.694, p = .006). Patients with >10% cortical interstitial inflammation had higher levels of uKIM-1 [4.9 (3.9, 5.5) vs. 0.8 (0.6, 1.5) mcg/mg, p = .001], MCP-1 [3.8 (2. 3, 4.2) vs. 0.7 (0.3, 1.2) mcg/mg, p = .001], sKIM-1 [9.2 (5.9, 32.7) vs. 1.4 (0, 3.5) pg/mL, p = .001], and lower sUMOD [8.7 (0, 39.7) vs. 46.1 (35.7, 53) ng/mL, p = .028]. CONCLUSION: The use of specific urinary and serum biomarkers of tubular dysfunction or injury may help to predict certain histologic parameters in LN patients.

Investigating child sexual abuse material availability, searches, and users on the anonymous Tor network for a public health intervention strategy.

Tor is widely used for staying anonymous online and accessing onion websites; unfortunately, Tor is popular for distributing and viewing illicit child sexual abuse material (CSAM). From 2018 to 2023, we analyse 176,683 onion domains and find that one-fifth share CSAM. We find that CSAM is easily available using 21 out of the 26 most-used Tor search engines. We analyse 110,133,715 search sessions from the Ahmia.fi search engine and discover that 11.1% seek CSAM. When searching CSAM by age, 40.5% search for 11-year-olds and younger; 11.0% for 12-year-olds; 8.2% for 13-year-olds; 11.6% for 14-year-olds; 10.9% for 15-year-olds; and 12.7% for 16-year-olds. We demonstrate accurate filtering for search engines, introduce intervention, show a questionnaire for CSAM users, and analyse 11,470 responses. 65.3% of CSAM users first saw the material when they were children themselves, and half of the respondents first saw the material accidentally, demonstrating the availability of CSAM. 48.1% want to stop using CSAM. Some seek help through Tor, and self-help websites are popular. Our survey finds commonalities between CSAM use and addiction. Help-seeking correlates with increasing viewing duration and frequency, depression, anxiety, self-harming thoughts, guilt, and shame. Yet, 73.9% of help seekers have not been able to receive it.

Tubular biomarkers in proteinuric kidney disease: histology correlation and kidney prognosis of tubular biomarkers.

Background: Proteinuria is not only a biomarker of chronic kidney disease (CKD) but also a driver of CKD progression. The aim of this study was to evaluate serum and urinary tubular biomarkers in patients with biopsied proteinuric kidney disease and to correlate them with histology and kidney outcomes. Methods: A single-center retrospective study was conducted on a cohort of 156 patients from January 2016 to December 2021. The following urinary and serum biomarkers were analyzed on the day of kidney biopsy: beta 2 microglobulin (ß2-mcg), alpha 1 microglobulin (α1-mcg), neutrophil gelatinase-associated lipocalin (NGAL), urinary kidney injury molecule-1 (uKIM-1), monocyte chemoattractant protein-1 (MCP-1), urinary Dickkopf-3 (uDKK3), uromodulin (urinary uUMOD), serum kidney injury molecule-1 (sKIM-1) and serum uromodulin (sUMOD). A composite outcome of kidney progression or death was recorded during a median follow-up period of 26 months. Results: Multivariate regression analysis identified sUMOD (ß-0.357, P < .001) and uDKK3 (ß 0.483, P < .001) as independent predictors of interstitial fibrosis, adjusted for age, estimated glomerular filtration rate (eGFR) and log proteinuria. Elevated levels of MCP-1 [odds ratio 15.61, 95% confidence interval (CI) 3.52-69.20] were associated with a higher risk of cortical interstitial inflammation >10% adjusted for eGFR, log proteinuria and microhematuria. Upper tertiles of uDKK3 were associated with greater eGFR decline during follow-up. Although not a predictor of the composite outcome, doubling of uDKK3 was a predictor of kidney events (hazard ratio 2.26, 95% CI 1.04-4.94) after adjustment for interstitial fibrosis, eGFR and proteinuria. Conclusions: Tubular markers may have prognostic value in proteinuric kidney disease, correlating with specific histologic parameters and identifying cases at higher risk of CKD progression.

A role for TREK1 in generating the slow afterhyperpolarization in developing starburst amacrine cells.

Slow afterhyperpolarizations (sAHPs) play an important role in establishing the firing pattern of neurons that in turn influence network activity. sAHPs are mediated by calcium-activated potassium channels. However, the molecular identity of these channels and the mechanism linking calcium entry to their activation are still unknown. Here we present several lines of evidence suggesting that the sAHPs in developing starburst amacrine cells (SACs) are mediated by two-pore potassium channels. First, we use whole cell and perforated patch voltage clamp recordings to characterize the sAHP conductance under different pharmacological conditions. We find that this conductance was calcium dependent, reversed at EK, blocked by barium, insensitive to apamin and TEA, and activated by arachidonic acid. In addition, pharmacological inhibition of calcium-activated phosphodiesterase reduced the sAHP. Second, we performed gene profiling on isolated SACs and found that they showed strong preferential expression of the two-pore channel gene kcnk2 that encodes TREK1. Third, we demonstrated that TREK1 knockout animals exhibited an altered frequency of retinal waves, a frequency that is set by the sAHPs in SACs. With these results, we propose a model in which depolarization-induced decreases in cAMP lead to disinhibition of the two-pore potassium channels and in which the kinetics of this biochemical pathway dictate the slow activation and deactivation of the sAHP conductance. Our model offers a novel pathway for the activation of a conductance that is physiologically important.

The Moderating Role of Health Variables on the Association between Physical Exercise and Quality of Life in Patients with End-Stage Renal Disease.

Scientific evidence demonstrates the positive impact that physical exercise has on the quality of life (QOL) of patients with chronic kidney disease (CKD). However, no study has proposed a model investigating the effect physical exercise has on the QOL of end-stage renal disease (ESRD) patients, considering the most frequent associated diseases (diabetes/hypertension). The objectives were (1) to explore the relationship between physical exercise and the QOL of adults with ESRD, and (2) to examine the moderating and/or mediating role of relevant patient variables. This non-interventional study utilized an ex post facto retrospective data analysis design with a sample of 310 patients with ESRD through two validated questionnaires. The dependent variables were the QOL scale (KDQOL-SF), and the physical function dimension (EFFISICA). The independent variables were the regular practice of intense physical activity (DEPINTE) and the daily time (in hours) the patient is in a sedentary attitude (TiParado). The moderating variables were the clinical situation and associated diseases. The mediator variable used was the body mass index. Bivariate and multiple regression analyses were conducted. Findings suggest implementing intense physical activity in transplant recipients and programmes to avoid sedentary lifestyles in dialysis patients have a positive effect in the QOL of ESRD patients.