Use of Antihypertensive Agents and Association With Risk of Adverse Outcomes in Chronic Kidney Disease: Focus on Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers.

Background Our objective was to determine patterns of antihypertensive agent use by stage of chronic kidney disease (CKD) and to evaluate the association between different classes of antihypertensive agents with nonrenal outcomes, especially in advanced CKD . Methods and Results We studied 3939 participants of the CRIC (Chronic Renal Insufficiency Cohort) study. Predictors were time-dependent angiotensin-converting enzyme inhibitor or angiotensin receptor blocker , β-blocker, and calcium channel blocker use (versus nonuse of agents in each class). Outcomes were adjudicated heart failure events or death. Adjusted Cox models were used to determine the association between predictors and outcomes. We also examined whether the associations differed based on the severity of CKD (early [stage 2-3 CKD ] versus advanced disease [stage 4-5 CKD ]). During median follow-up of 7.5 years, renin-angiotensin-aldosterone system inhibitor use plateaued during CKD stage 3 (75%) and declined to 37% by stage 5, while β-blocker, calcium channel blocker, and diuretic use increased steadily with advancing CKD . Renin-angiotensin-aldosterone system inhibitor use was associated with lower risk of heart failure (hazard ratio, 0.79; 95% confidence interval, 0.67-0.97) and death (hazard ratio, 0.78; 95% confidence interval, 0.67-0.90), regardless of severity of CKD . Calcium channel blocker use was not associated with risk of heart failure or death, regardless of the severity of CKD . β-Blocker use was associated with higher risk of heart failure (hazard ratio, 1.62; 95% confidence interval, 1.29-2.04) and death (hazard ratio, 1.22; 95% confidence interval, 1.03-1.43), especially during early CKD ( P<0.05 for interaction). Conclusions Angiotensin-converting enzyme inhibitor and angiotensin receptor blocker use decreased, while use of other agents increased with advancing CKD . Use of agents besides angiotensin-converting enzyme inhibitors or angiotensin receptor blockers may be associated with suboptimal outcomes in patients with CKD

Interstitial inflammation and fibrosis in rats with diet-induced hypercholesterolemia

Interstitial inflammation and fibrosis in rats with diet-induced hypercholesterolemia. Abnormalities in lipid metabolism appear to play a pathogenic role in progressive renal disease. To elucidate the cellular and molecular basis of renal interstitial fibrosis in uninephrectomized rats with diet-induced hypercholesterolemia, we fed experimental rats with standard rat chow supplemented with 4% cholesterol and 1% cholic acid. Control rats were fed an isocaloric diet. Groups of 7 control and 7 experimental rats were killed after 4, 8, and 12 weeks. Hypercholesterolemic rats developed albuminuria; serum creatinine was elevated at 12 weeks. By 12 weeks numerous oil red O-positive cells were present throughout the interstitium and to a lesser extent in tubules. Total renal lipid-peroxidation products were significantly increased (172 ± 15, 198 ± 28, and 197 ± 13mmol malondialdehyde/kidney at 4, 8, and 12 weeks vs. 123 ± 17, 144 ± 6, and 125 ± 10mmol in controls). Immunostaining revealed oxidatively modified lipoproteins within tubular and interstitial cells. The interstitial disease was characterized by an interstitial infiltrate of monocytes. Significant increases were detected in renal cortical mRNA levels for monocyte chemoattractant protein-1 (MCP-1), osteopontin, and vascular cell adhesion molecule-1 (VCAM-1), associated with changes in the pattern of immunostaining for each encoded proteins. Total kidney collagen was significantly increased at 12 weeks (9.8 ± 0.9mg/kidney vs. 7.8 ± 0.9mg in controls). At 12 weeks there was a significant increase in interstitial immunostaining for collagen I, collagen III, collagen IV, fibronectin and tenascin. A significant threefold increase in renal cortical mRNA levels for transforming growth factor beta-1 (TGF-β1) at 4 and 12 weeks was associated with the appearance of TGF-β1-positive interstitial cells. Renal matrix protein mRNA levels were measured at 4, 8, and 12 weeks. The only statistically significant elevations were procollagen α1(I) and procollagen α1(III) at weeks 8 and 12. In contrast, renal cortical mRNA levels for the tissue inhibitor of metalloproteinases-1 (TIMP-1) were significantly increased at 4, 8 and 12 weeks (1.4 ± 0.5, 2.7 ± 0.9 and 2.7 ± 1.4 arbitrary densitometric units, respectively, vs. 1.0 ± 0.4, 1.0 ± 0.5 and 1.0 ± 0.4 units for controls), and urokinase-type plasminogen activator (μPA) mRNA levels were significantly decreased at 4, 8, and 12 weeks (0.4 ± 0.1 arbitrary densitometric units for all three experimental groups vs. 1.0 ± 0.4, 1.0 ± 0.3, and 1.0 ± 0.4 units for the control groups). In summary, rats with diet-induced hypercholesterolemia develop renal interstitial fibrosis over several weeks. Following the accumulation of lipids within tubulointerstitial cells, interstitial nephritis develops. The fibrotic phase is characterized by modest changes in matrix protein mRNA levels, up-regulated TIMP-1, and down-regulated μPA levels, suggesting that altered matrix degradation plays a role in the interstitial fibrogenesis in this model

Functional compartmentalization of Rad9 and Hus1 reveals diverse assembly of the 9-1-1 complex components during the DNA damage response in Leishmania

The Rad9-Rad1-Hus1 (9-1-1) complex is a key component in the coordination of DNA damage sensing, cell cycle progression and DNA repair pathways in eukaryotic cells. This PCNA-related trimer is loaded onto RPA-coated single stranded DNA and interacts with ATR kinase to mediate effective checkpoint signaling to halt the cell cycle and to promote DNA repair. Beyond these core activities, mounting evidence suggests that a broader range of functions can be provided by 9-1-1 structural diversification. The protozoan parasite Leishmania is an early-branching eukaryote with a remarkably plastic genome, which hints at peculiar genome maintenance mechanisms. Here, we investigated the existence of homologs of the 9-1-1 complex subunits in L. major and found that LmRad9 and LmRad1 associate with chromatin in response to replication stress and form a complex in vivo with LmHus1. Similar to LmHus1, LmRad9 participates in telomere homeostasis and in the response to both replication stress and double strand breaks. However, LmRad9 and LmHus1-deficient cells present markedly opposite phenotypes, which suggest their functional compartmentalization. We show that some of the cellular pool of LmRad9 forms an alternative complex and that some of LmHus1 exists as a monomer. We propose that the diverse assembly of the Leishmania 9-1-1 subunits mediates functional compartmentalization, which has a direct impact on the response to genotoxic stress

Tubular secretion of creatinine and kidney function: an observational study.

BackgroundPrior papers have been inconsistent regarding how much creatinine clearance (CrCl) overestimates glomerular filtration rate (GFR). A recent cross-sectional study suggested that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio is larger when GFR is lower among patients with chronic kidney disease (CKD); but there have been no validation of this in other cohorts.MethodsTo fill these gaps in knowledge regarding the relation between CrCl and GFR, we conducted cross-sectional and longitudinal analysis of the Modification of Diet in Renal Disease study (MDRD) and African American Study of Kidney Disease and Hypertension (AASK); and cross-sectional analysis of a clinical dataset from the Mayo Clinic of four different patient populations (CKD patients, kidney transplant recipients, post kidney donation subgroup and potential kidney donors). In the cross-sectional analyses (MDRD, AASK and Mayo Clinic cohort), we examined the relation between the CrCl/iothalamate GFR (iGFR) ratio at different categories of iGFR or different levels of CrCl. In the MDRD and AASK longitudinal analyses, we studied how the CrCl/iGFR ratio changed with those who had improvement in iGFR (CrCl) over time versus those who had worsening of iGFR (CrCl) over time.ResultsObserved CrCl/iGFR ratios were generally on the lower end of the range reported in the literature for CKD (median 1.24 in MDRD, 1.13 in AASK and 1.25 in Mayo Clinic cohort). Among CKD patients in whom CrCl and iGFR were measured using different timed urine collections, CrCl/iGFR ratio were higher with lower iGFR categories but lower with lower CrCl categories. However, among CKD patients in whom CrCl and iGFR were measured using the same timed urine collections (which reduces dis-concordant measurement error), CrCl/iGFR ratio were higher with both lower iGFR categories and lower CrCl categories.ConclusionsThese data refute the recent suggestion that measurement error alone could entirely account for the longstanding observation that CrCl/GFR ratio increases as GFR decreases in CKD patients. They also highlight the lack of certainty in our knowledge with regard to how much CrCl actually overestimates GFR

Association Between Blood Pressure and Adverse Renal Events in Type 1 Diabetes.

ObjectiveTo compare different blood pressure (BP) levels in their association with the risk of renal outcomes in type 1 diabetes and to determine whether an intensive glycemic control strategy modifies this association.Research design and methodsWe included 1,441 participants with type 1 diabetes between the ages of 13 and 39 years who had previously been randomized to receive intensive versus conventional glycemic control in the Diabetes Control and Complications Trial (DCCT). The exposures of interest were time-updated systolic BP (SBP) and diastolic BP (DBP) categories. Outcomes included macroalbuminuria (>300 mg/24 h) or stage III chronic kidney disease (CKD) (sustained estimated glomerular filtration rate <60 mL/min/1.73 m2).ResultsDuring a median follow-up time of 24 years, there were 84 cases of stage III CKD and 169 cases of macroalbuminuria. In adjusted models, SBP in the <120 mmHg range was associated with a 0.59 times higher risk of macroalbuminuria (95% CI 0.37-0.95) and a 0.32 times higher risk of stage III CKD (95% CI 0.14-0.75) compared with SBPs between 130 and 140 mmHg. DBP in the <70 mmHg range were associated with a 0.73 times higher risk of macroalbuminuria (95% CI 0.44-1.18) and a 0.47 times higher risk of stage III CKD (95% CI 0.21-1.05) compared with DBPs between 80 and 90 mmHg. No interaction was noted between BP and prior DCCT-assigned glycemic control strategy (all P > 0.05).ConclusionsA lower BP (<120/70 mmHg) was associated with a substantially lower risk of adverse renal outcomes, regardless of the prior assigned glycemic control strategy. Interventional trials may be useful to help determine whether the currently recommended BP target of 140/90 mmHg may be too high for optimal renal protection in type 1 diabetes

Effect of Blood Pressure Control on Long-Term Risk of End-Stage Renal Disease and Death Among Subgroups of Patients With Chronic Kidney Disease.

Background Our objective was to explore the effect of intensive blood pressure (BP) control on kidney and death outcomes among subgroups of patients with chronic kidney disease divided by baseline proteinuria, glomerular filtration rate, age, and body mass index. Methods and Results We included 840 MDRD (Modification of Diet in Renal Disease) trial and 1067 AASK (African American Study of Kidney Disease and Hypertension) participants. We used Cox models to examine whether the association between intensive BP control and risk of end-stage renal disease (ESRD) or death is modified by baseline proteinuria (≥0.44 versus <0.44 g/g), glomerular filtration rate (≥30 versus <30 mL/min per 1.73 m2), age (≥40 versus <40 years), or body mass index (≥30 versus <30 kg/m2). The median follow-up was 14.9 years. Strict (versus usual) BP control was protective against ESRD (hazard ratio [HR]ESRD, 0.77; 95% CI, 0.64-0.92) among those with proteinuria ≥0.44 g/g but not proteinuria <0.44 g/g. Strict (versus usual) BP control was protective against death (HRdeath, 0.73; 95% CI, 0.59-0.92) among those with glomerular filtration rate <30 mL/min per 1.73 m2 but not glomerular filtration rate ≥30 mL/min per 1.73 m2 (HRdeath, 0.98; 95% CI, 0.84-1.15). Strict (versus usual) BP control was protective against ESRD among those ≥40 years (HRESRD, 0.82; 95% CI, 0.71-0.94) but not <40 years. Strict (versus usual) BP control was also protective against ESRD among those with body mass index ≥30 kg/m2 (HRESRD, 0.75; 95% CI, 0.61-0.92) but not body mass index <30 kg/m2. Conclusions The ESRD and all-cause mortality benefits of intensive BP lowering may not be uniform across all subgroups of patients with chronic kidney disease. But intensive BP lowering was not associated with increased risk of ESRD or death among any subgroups that we examined

Importance of external quality assessment for SARS-CoV-2 antigen detection during the COVID-19 pandemic

Background: Antigen testing has become an essential part of fighting the ongoing COVID-19 pandemic. With the continual increase in available tests, independent and extensive comparative evaluations using data from external quality assessment (EQA) studies to evaluate test performance between different users are required.Objectives: An EQA scheme was established to assess the sensitivity of antigen tests and the potential impact of circulating SARS-CoV-2 strains on their performance.Study design: Panels were prepared for three challenges in 2021 containing inactivated SARS-CoV-2-positive samples of various genetic strains (including variants of concern, VOCs) at different concentrations, and negative samples. Data was analysed based on qualitative testing results in relation to the antigen test used. Results: Participants registered for each individual challenge in any combination. In total, 258 respondents from 27 countries worldwide were counted submitting 472 datasets. All core samples were correctly reported by 76.7 to 83.1% at participant level and by 73.5 to 83.8% at dataset level. Sensitivity differences could be shown in viral loads and SARS-CoV-2 strains/variants including the impact on performance by a B.1.1.7-like mutant strain with a deletion in the nucleoprotein gene. Lateral flow rapid antigen tests showed a higher rate of false negatives in general compared with automated point-of-care tests and laboratory ELISA/immunoassays.Conclusions: EQA schemes can provide valuable data to inform participants about weaknesses in their testing process or methods and support ongoing assay evaluations for regulatory approval or post-market surveillance

The effects of social service contact on teenagers in England

Objective: This study investigated outcomes of social service contact during teenage years. Method: Secondary analysis was conducted of the Longitudinal Survey of Young People in England (N = 15,770), using data on reported contact with social services resulting from teenagers’ behavior. Outcomes considered were educational achievement and aspiration, mental health, and locus of control. Inverse-probability-weighted regression adjustment was used to estimate the effect of social service contact. Results: There was no significant difference between those who received social service contact and those who did not for mental health outcome or aspiration to apply to university. Those with contact had lower odds of achieving good exam results or of being confident in university acceptance if sought. Results for locus of control were mixed. Conclusions: Attention is needed to the role of social services in supporting the education of young people in difficulty. Further research is needed on the outcomes of social services contact

The Australia Telescope 20 GHz Survey: The Source Catalogue

We present the full source catalogue from the Australia Telescope 20 GHz (AT20G) Survey. The AT20G is a blind radio survey carried out at 20 GHz with the Australia Telescope Compact Array (ATCA) from 2004 to 2008, and covers the whole sky south of declination 0 deg. The AT20G source catalogue presented here is an order of magnitude larger than any previous catalogue of high-frequency radio sources, and includes 5890 sources above a 20 GHz flux-density limit of 40 mJy. All AT20G sources have total intensity and polarisation measured at 20 GHz, and most sources south of declination -15 deg also have near-simultaneous flux-density measurements at 5 and 8 GHz. A total of 1559 sources were detected in polarised total intensity at one or more of the three frequencies. We detect a small but significant population of non-thermal sources that are either undetected or have only weak detections in low-frequency catalogues. We introduce the term Ultra-Inverted Spectrum (UIS) to describe these radio sources, which have a spectral index alpha(5, 20) > +0.7 and which constitute roughly 1.2 per cent of the AT20G sample. The 20 GHz flux densities measured for the strongest AT20G sources are in excellent agreement with the WMAP 5-year source catalogue of Wright et al. (2009), and we find that the WMAP source catalogue is close to complete for sources stronger than 1.5 Jy at 23 GHz.Comment: 21 pages, accepted for publication in MNRA

The neighbourhood environment and use of neighbourhood resources in older adults with and without lower limb osteoarthritis:results from the Hertfordshire Cohort Study

This study aimed to examine the associations of perceptions of neighbourhood cohesion and neighbourhood problems and objectively measured neighbourhood deprivation with the use of neighbourhood resources by older adults with and without lower limb osteoarthritis (LLOA), and to assess whether these relationships are stronger in older persons with LLOA than in those without the condition. Data from the Hertfordshire Cohort Study were used. American College of Rheumatology classification criteria were used to diagnose clinical LLOA (knee and/or hip osteoarthritis). Use of neighbourhood resources was assessed using the Home and Community Environment instrument. Participants were asked about their perceptions of neighbourhood cohesion and neighbourhood problems. Objective neighbourhood deprivation was assessed using the Index of Multiple Deprivation score based on 2010 census data. Of the 401 participants (71–80 years), 74 (18.5 %) had LLOA. The neighbourhood measures were not significantly associated with use of resources in the full sample. A trend for a negative association between use of public transport and perceived neighbourhood problems was observed in participants with LLOA (OR = 0.77, 99 % CI = 0.53–1.12), whereas a trend for a positive association between perceived neighbourhood problems and use of public transport was found in participants without LLOA (OR = 1.18, 99 % CI = 1.00–1.39). The perception of more neighbourhood problems seems only to hinder older adults with LLOA to make use of public transport. Older adults with LLOA may be less able to deal with neighbourhood problems and more challenging environments than those without the condition