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Background: Idiopathic membranous nephropathy remains the leading cause of nephrotic syndrome in Caucasian adults. Immunosuppressive therapy with cyclosporine (CSA) is often successful in reducing proteinuria, but its use is associated with a high relapse rate. Rituximab, a monoclonal antibody that specifically targets CD20 on the surface of B-cells, is effective in achieving a complete remission of proteinuria in patients with idiopathic membranous nephropathy. However, whether rituximab is as effective as CSA in inducing and maintaining complete or partial remission of proteinuria in these patients is unknown. The membranous nephropathy trial of rituximab (MENTOR) hypothesizes that B-cell targeting with rituximab is non-inferior to CSA in inducing long-term remission of proteinuria. Methods and Design: Patients with idiopathic membranous nephropathy, proteinuria ≥5 g/24 h, and a minimum of 3 months of Angiotensin-II blockade will be randomized into a 12-month treatment period with IV rituximab, 1,000 mg (2 infusions, 14 days apart; repeated at 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months) or oral CSA 3.5-5 mg/kg/day for 6 months (continued for another 6 months if a substantial reduction in proteinuria (equal to or >25%) is seen at 6 months). The efficacy of treatment will be assessed by the remission status (based on changes in proteinuria) at 24 months from randomization. Patient safety will be assessed via collection of adverse event data and evaluation of pre- and posttreatment laboratory data. At the 6-month post-randomization visit, patients who have been randomized to either CSA or rituximab but who do not have a reduction in proteinuria ≥25% (confirmed on repeat measurements within 2 weeks) will be considered treatment failures and exit the study. Discussion: This study will test for the first time whether treatment with rituximab is non-inferior to CSA in inducing long-term remission (complete or partial) of proteinuria in patients with idiopathic membranous nephropathy.

In a randomized, controlled trial involving patients with membranous nephropathy, rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission for up to 24 months.

Mouse kidney expresses mRNA of four highly related sodium-glucose cotransporters: Regulation by cadmium. To study the molecular mechanism responsible for cadmium-induced Fanconi syndrome, an in vitro mouse model has been used. We have previously shown that exposure of primary cultures of kidney cortical cells to micromolar concentrations of cadmium inhibited uptake of the glucose analog, [14C] methyl α-D-glucopyranoside (AMG) (261 mCi/mmol, NEN), and decreased mRNA levels of two kidney sodium-glucose cotransporters (SGLTs), SGLT1 and SGLT2. We also isolated partial cDNA of another member of the SGLT family, SGLT3-b, from cultured kidney cells and observed that cadmium exposure increased the abundance of its mRNA. In this study, we investigated the effect of cadmium on the second mouse kidney SGLT3 isoform, SGLT3-a. We also examined which SGLTs were transcribed in vivo. Cadmium was added to the confluent primary cultures of kidney cortical cells at concentrations of 5, 7.5, and 10 μmol/L. After 24 hours, uptake of [14C]AMG was measured and total RNA was extracted for semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) of SGLT3-a. Also, cDNA from whole kidneys of mice was used in PCR with primers specific for each SGLT. A partial cDNA sequence of SGLT3-a and the full-length cDNA sequence of SGLT3-b were obtained from their respective PCR clones. Exposure of cortical cells to 5 μmol/L cadmium increased SGLT3-a mRNA level 3.4- ± 0.78-fold (mean ± SEM, P < 0.03, N = 5). mRNAs of SGLT1, SGLT2, SGLT3-a, and SGLT3-b were simultaneously present in cDNA samples from whole kidneys of mice. SGLT3-b cDNA sequence was revised from its predicted sequence to encode a 660 amino acid protein. Reabsorption of glucose in mouse kidney may involve four SGLTs. Cadmium affects mRNA expression of all four SGLTs in vitro.

To the Editor: Tiebosch and colleagues (Jan. 5 issue) 1 have drawn attention to thin-basement-membrane nephropathy as a common but neglected cause of hematuria in adults. The condition is almost invariably familial, and despite earlier impressions, 2 we sometimes find associated nerve deafness, albeit often slight and requiring audiometry for detection. A subnormal harmonic mean thickness of the glomerular basement membrane is an important criterion, but we note, with the experience of some 50 cases, that the values in patients with apparent thinning overlap those at the lower end of the normal range. Hence, a low normal result may not exclude the . . . No extract is available for articles shorter than 400 words.

We deduce almost-sure exponentially fast mixing of passive scalars advected by solutions of the stochastically-forced 2D Navier–Stokes equations and 3D hyper-viscous Navier–Stokes equations in 𝕋 d subjected to nondenegenerate Hσ -regular noise for any σ sufficiently large. That is, for all s > 0 there is a deterministic exponential decay rate such that all mean-zero Hs passive scalars decay in H−s at this same rate with probability one. This is equivalent to what is known as quenched correlation decay for the Lagrangian flow in the dynamical systems literature. This is a follow-up to our previous work, which establishes a positive Lyapunov exponent for the Lagrangian flow—in general, almost-sure exponential mixing is much stronger than this. Our methods also apply to velocity fields evolving according to finite-dimensional models, for example, Galerkin truncations of Navier–Stokes or the Stokes equations with very degenerate forcing. For all 0 ≤ k < ∞, this exhibits many examples of C t k C x ∞ random velocity fields that are almost-sure exponentially fast mixers.

A large stable isotope dataset from East and Central Africa from ca. 30 regional collection sites that range from forest to grassland shows that most extant East and Central African large herbivore taxa have diets dominated by C₄ grazing or C₃ browsing. Comparison with the fossil record shows that faunal assemblages fromca.4.1–2.35 Ma in the Turkana Basin had a greater diversity of C₃–C₄ mixed feeding taxa than is presently found in modern East and Central African environments. In contrast, the period from 2.35 to 1.0 Ma had more C₄-grazing taxa, especially nonruminant C₄-grazing taxa, than are found in modern environments in East and Central Africa. Many nonbovid C₄ grazers became extinct in Africa, notably the suidNotochoerus,the hipparion equidEurygnathohippus,the giraffidSivatherium,and the elephantidElephas.Other important nonruminant C₄-grazing taxa switched to browsing, including suids in the lineageKolpochoerus-Hylochoerusand the elephantLoxodonta.Many modern herbivore taxa in Africa have diets that differ significantly from their fossil relatives. Elephants and tragelaphin bovids are two groups often used for paleoecological insight, yet their fossil diets were very different from their modern closest relatives; therefore, their taxonomic presence in a fossil assemblage does not indicate they had a similar ecological function in the past as they do at present. Overall, we find ecological assemblages of C₃-browsing, C₃–C₄-mixed feeding, and C₄-grazing taxa in the Turkana Basin fossil record that are different from any modern ecosystem in East or Central Africa.

Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in non-diabetic Caucasian adults over 40 years of age. It has an estimated incidence of 8–10 cases per 1 million. Fifty per cent of patients diagnosed with primary MN continue to have nephrotic syndrome and 30% of patients may progress to end-stage renal disease over 10 years. Although it was recognised as a distinct clinic-pathological entity in 1940s by immunofluorescence and electron microscopy, the pathogenesis and treatment have become more apparent only in the last decade. Discovery of M-type phospholipase A2 receptor (PLA2R) antibodies and thrombospondin type 1 domain-containing 7A antibodies has given new perspectives in understanding the pathogenesis of the disease process. Anti-PLA2R antibody is the first serologic marker that has promising evidence to be used as a tool to prognosticate the course of the disease. More importantly, therapeutic agents such as rituximab and adrenocorticotropic hormone analogues are the newer therapeutic options that should be considered in the therapy of primary MN.

Background: Alternatives to the Friedewald low-density lipoprotein cholesterol (LDL-C) equation have been proposed. Objective: To compare the accuracy of available LDL-C equations with ultracentrifugation measurement. Methods: We used the second harvest of the Very Large Database of Lipids (VLDbL), which is a population-representative convenience sample of adult and pediatric patients (N = 5,051,467) with clinical lipid measurements obtained via the vertical auto profile (VAP) ultracentrifugation method between October 1, 2015 and June 30, 2019. We performed a systematic literature review to identify available LDL-C equations and compared their accuracy according to guideline-based classification. We also compared the equations by their median error versus ultracentrifugation. We evaluated LDL-C equations overall and stratified by age, sex, fasting status, and triglyceride levels, as well as in patients with atherosclerotic cardiovascular disease, hypertension, diabetes, kidney disease, inflammation, and thyroid dysfunction. Results: Analyzing 23 identified LDL-C equations in 5,051,467 patients (mean±SD age, 56±16 years; 53.3% women), the Martin/Hopkins equation most accurately classified LDL-C to the correct category (89.6%), followed by the Sampson (86.3%), Chen (84.4%), Puavilai (84.1%), Delong (83.3%), and Friedewald (83.2%) equations. The other 17 equations were less accurate than Friedewald, with accuracy as low as 35.1%. The median error of equations ranged from –10.8 to 18.7 mg/dL, and was best optimized using the Martin/Hopkins equation (0.3, IQR–1.6 to 2.4 mg/dL). The Martin/Hopkins equation had the highest accuracy after stratifying by age, sex, fasting status, triglyceride levels, and clinical subgroups. In addition, one in five patients who had Friedewald LDL-C <70 mg/dL, and almost half of the patients with Friedewald LDL-C <70 mg/dL and triglyceride levels 150–399 mg/dL, had LDL-C correctly reclassified to >70 mg/dL by the Martin/Hopkins equation. Conclusions: Most proposed alternatives to the Friedewald equation worsen LDL-C accuracy, and their use could introduce unintended disparities in clinical care. The Martin/Hopkins equation demonstrated the highest LDL-C accuracy overall and across subgroups.

Local adaptation may facilitate range expansion during invasions, but the mechanisms underlying successful invasions remain unclear. Cheatgrass ( Bromus tectorum ), native to Eurasia and Africa, has invaded globally, with severe impacts in western North America. We aim to identify mechanisms and consequences of local adaptation in the North American cheatgrass invasion. We sequence 307 range-wide genotypes and conduct controlled experiments. We find that diverse lineages invaded North America, where long-distance gene flow is common. Nearly half of North American cheatgrass comprises a mosaic of ~19 locally adapted, near-clonal genotypes, each seemingly very successful in a different part of North America. Additionally, ancestry, phenotype, and allele frequency-environment clines in the native range predict those in the invaded range, indicating pre-adapted genotypes colonized different regions. Common gardens show directional selection on flowering time that reverse between warm and cold sites, potentially maintaining clines. In the USA Great Basin, genomic predictions of strong local adaptation identify sites where cheatgrass is most dominant. Our results indicate that multiple introductions and migration within the invaded range fuel local adaptation and success of cheatgrass in western North America. Understanding how environment and gene flow shape adaptation and invasion is critical for managing ongoing invasions. Here, the authors examine the mechanisms behind cheatgrass’s successful invasion of North American ecosystems. Their genetic analyses and common garden experiments demonstrate that multiple introductions and migrations facilitated cheatgrass local adaptation.

Short-term treatment for people with type 2 diabetes using a low dose of the selective endothelin A receptor antagonist atrasentan reduces albuminuria without causing significant sodium retention. We report the long-term effects of treatment with atrasentan on major renal outcomes. We did this double-blind, randomised, placebo-controlled trial at 689 sites in 41 countries. We enrolled adults aged 18–85 years with type 2 diabetes, estimated glomerular filtration rate (eGFR) 25–75 mL/min per 1·73 m2 of body surface area, and a urine albumin-to-creatinine ratio (UACR) of 300–5000 mg/g who had received maximum labelled or tolerated renin–angiotensin system inhibition for at least 4 weeks. Participants were given atrasentan 0·75 mg orally daily during an enrichment period before random group assignment. Those with a UACR decrease of at least 30% with no substantial fluid retention during the enrichment period (responders) were included in the double-blind treatment period. Responders were randomly assigned to receive either atrasentan 0·75 mg orally daily or placebo. All patients and investigators were masked to treatment assignment. The primary endpoint was a composite of doubling of serum creatinine (sustained for ≥30 days) or end-stage kidney disease (eGFR <15 mL/min per 1·73 m2 sustained for ≥90 days, chronic dialysis for ≥90 days, kidney transplantation, or death from kidney failure) in the intention-to-treat population of all responders. Safety was assessed in all patients who received at least one dose of their assigned study treatment. The study is registered with ClinicalTrials.gov, number NCT01858532. Between May 17, 2013, and July 13, 2017, 11 087 patients were screened; 5117 entered the enrichment period, and 4711 completed the enrichment period. Of these, 2648 patients were responders and were randomly assigned to the atrasentan group (n=1325) or placebo group (n=1323). Median follow-up was 2·2 years (IQR 1·4–2·9). 79 (6·0%) of 1325 patients in the atrasentan group and 105 (7·9%) of 1323 in the placebo group had a primary composite renal endpoint event (hazard ratio [HR] 0·65 [95% CI 0·49–0·88]; p=0·0047). Fluid retention and anaemia adverse events, which have been previously attributed to endothelin receptor antagonists, were more frequent in the atrasentan group than in the placebo group. Hospital admission for heart failure occurred in 47 (3·5%) of 1325 patients in the atrasentan group and 34 (2·6%) of 1323 patients in the placebo group (HR 1·33 [95% CI 0·85–2·07]; p=0·208). 58 (4·4%) patients in the atrasentan group and 52 (3·9%) in the placebo group died (HR 1·09 [95% CI 0·75–1·59]; p=0·65). Atrasentan reduced the risk of renal events in patients with diabetes and chronic kidney disease who were selected to optimise efficacy and safety. These data support a potential role for selective endothelin receptor antagonists in protecting renal function in patients with type 2 diabetes at high risk of developing end-stage kidney disease. AbbVie.