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Background Insulin resistance (IR) is a pathophysiologic hallmark of type 2 diabetes and associated with the presence of chronic kidney disease (CKD). Experimental studies suggest that endothelin-1 increases IR. We assessed the association between IR and cardio-renal outcomes and the effect of the selective endothelin receptor antagonist atrasentan on IR in patients with type 2 diabetes and CKD. Methods We used data from the RADAR and SONAR trials that recruited participants with type 2 diabetes and CKD [eGFR 25–75 mL/min/1.73 m², urine albumin-to-creatinine ratio of 300–5000 mg/g]. IR was calculated using the homeostatic model assessment (HOMA-IR). The association between HOMA-IR and the pre-specified cardio-renal outcomes was assessed using multivariable Cox proportional hazards regression, and effects of atrasentan on HOMA-IR by a linear mixed effect model. Results In the SONAR trial, each log-unit increase in HOMA-IR was associated with an increased risk of the composite cardio-renal outcome [hazard ratio 1.32 (95%CI 1.09,1.60; p = 0.004)], kidney outcome [hazard ratio 1.30 (95%CI 1.00,1.68; p-value = 0.048)], and the kidney or all-cause mortality outcome [hazard ratio 1.25 (95%CI 1.01,1.55; p-value = 0.037)]. After 12 weeks treatment in the RADAR trial (N = 123), atrasentan 0.75 mg/day and 1.25 mg/day compared to placebo reduced HOMA-IR by 19.1 (95%CI -17.4, 44.3) and 26.7% (95%CI -6.4, 49.5), respectively. In the SONAR trial (N = 1914), atrasentan 0.75 mg/day compared to placebo reduced HOMA-IR by 9.6% (95%CI 0.6, 17.9). Conclusions More severe IR is associated with increased risk of cardio-renal outcomes. The endothelin receptor antagonist atrasentan reduced IR. Trial registration RADAR trial (Reducing Residual Albuminuria in Subjects With Diabetes and Nephropathy With AtRasentan): NCT01356849. SONAR trial (The Study Of Diabetic Nephropathy With AtRasentan) NCT01858532.

•Acupuncture, acupressure and topical capsaicin were effective for uremic pruritus.•Omega-3 fatty acids and zinc showed mixed efficacy in treating uremic pruritus.•Larger trials are needed to evaluate efficacy of complementary alternative medicine. Uremic pruritus (UP) is one of the most bothersome symptoms among chronic kidney disease (CKD) patients. The pathophysiology of UP remains elusive, resulting in limited treatment options. The inability of standard medical treatments to provide effective relief has piqued interest in complementary and alternative medicine (CAM). A systematic review of randomized controlled trials (RCTs) summarizing the efficacy and safety profile of CAM used for UP in CKD patients was performed. CAM interventions were classified using categories proposed by the National Center for Complementary and Integrative Health. The efficacy of each CAM was determined from changes in UP severity and all reported adverse effects were extracted. Of 5242 articles screened, 34 RCTs were included, with 15 (44.1 %) studies having a sample size greater than 50. The studies considered 21 treatments including omega-3 fatty acid supplementation (n=5), acupuncture (n=5), topical capsaicin (n=4) and acupressure (n=3). Acupuncture, acupressure and topical capsaicin were shown to be effective in improving uremic pruritus. Interventions which include oral omega-3 fatty acid and zinc supplementation demonstrated mixed efficacy. Other therapies such as evening primrose oil, turmeric, vitamin B3, vitamin D and thermal therapy were not effective for treatment of UP. Common adverse effects reported with topical capsaicin included mild burning sensations (50.0–88.2 %) or erythema (6.7–22.7%) while that of acupuncture included soreness (7.5 %), bleeding (6.0–7.5%) and hematoma (1.9 %). Acupuncture, acupressure and topical capsaicin have the largest body of evidence for efficacy in the treatment of UP. Larger and higher quality RCTs are required to examine the efficacy and safety of promising CAM.

ObjectivePatients with advanced chronic kidney disease (CKD) or kidney failure receiving replacement therapy (KFRT) are highly vulnerable to COVID-19 infection, morbidity and mortality. Vaccination is effective, but access differs around the world. We aimed to ascertain the availability, readiness and prioritisation of COVID-19 vaccines for this group of patients globally.Setting and participantsCollaborators from the International Society of Nephrology (ISN), Dialysis Outcomes and Practice Patterns Study and ISN-Global Kidney Health Atlas developed an online survey that was administered electronically to key nephrology leaders in 174 countries between 2 July and 4 August 2021.ResultsSurvey responses were received from 99 of 174 countries from all 10 ISN regions, among which 88/174 (50%) were complete. At least one vaccine was available in 96/99 (97%) countries. In 71% of the countries surveyed, patients on dialysis were prioritised for vaccination, followed by patients living with a kidney transplant (KT) (62%) and stage 4/5 CKD (51%). Healthcare workers were the most common high priority group for vaccination. At least 50% of patients receiving in-centre haemodialysis, peritoneal dialysis or KT were estimated to have completed vaccination at the time of the survey in 55%, 64% and 51% of countries, respectively. At least 50% of patients in all three patient groups had been vaccinated in >70% of high-income countries and in 100% of respondent countries in Western Europe.The most common barriers to vaccination of patients were vaccine hesitancy (74%), vaccine shortages (61%) and mass vaccine distribution challenges (48%). These were reported more in low-income and lower middle-income countries compared with high-income countries.ConclusionPatients with advanced CKD or KFRT were prioritised in COVID-19 vaccination in most countries. Multiple barriers led to substantial variability in the successful achievement of COVID-19 vaccination across the world, with high-income countries achieving the most access and success.

In a prespecified interim analysis of a phase 3, randomized, controlled trial, the selective endothelin type A receptor antagonist atrasentan reduced proteinuria in patients with IgA nephropathy, without apparent safety issues.

Endothelin-1 is a potent vasoconstrictor that has diverse physiological functions in the kidney, including in the regulation of blood flow and glomerular filtration, electrolyte homeostasis and endothelial function. Overexpression of endothelin-1 contributes to the pathophysiology of both diabetic and non-diabetic chronic kidney disease (CKD). Selective endothelin receptor antagonists (ERAs) that target the endothelin A (ET A ) receptor have demonstrated benefits in animal models of kidney disease and in clinical trials. In patients with type 2 diabetes and CKD, the selective ET A ERA, atrasentan, reduced albuminuria and kidney function decline. Concerns about the increased risks of fluid retention and heart failure with ERA use have led to the design of further trials to optimize dosing and patient selection. More recent studies have shown that the dual ET A  receptor and angiotensin receptor blocker, sparsentan, preserved kidney function with minimal fluid retention in patients with IgA nephropathy. Moreover, combined administration of a low dose of the ET A -selective ERA, zibotentan, with the sodium–glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin, enhanced albuminuria reduction and mitigated fluid retention in patients with CKD. Notably, sparsentan and aprocitentan have received FDA approval for the treatment of IgA nephropathy and treatment-resistant hypertension, respectively. This Review describes our current understanding of the use of ERAs in patients with CKD to guide their optimal safe and effective use in clinical practice. Endothelin-1 (ET-1) is a potent vasoactive peptide that is produced by various cell types of the kidney and regulates a variety of physiological processes. This Review describes the role of ET-1 in the kidney and in the development of chronic kidney disease, and the kidney-protective effects of endothelin-receptor antagonists in preclinical and clinical studies. Key points Endothelin-1 is a potent vasoactive peptide that acts through two G protein-coupled receptor subtypes, the ET A and ET B receptors. Endothelin-1 is produced by various kidney cell types such as endothelial cells, mesangial cells and podocytes and has physiological roles in processes such as blood pressure control, fluid and electrolyte homeostasis, and glomerular filtration. Increased levels of endothelin-1, primarily through activation of ET A receptor signalling, induces pathogenic effects such as vasoconstriction, inflammation, fibrosis, and cell proliferation within the kidney. ET A receptor-selective endothelin receptor antagonists (ERAs) have shown benefits in preclinical kidney disease models of IgA nephropathy, focal segmental glomerular sclerosis and diabetic kidney disease. ERAs have been shown to reduce proteinuria and have demonstrated kidney-protective effects in both diabetic- and non-diabetic kidney disease; clinical trials are currently underway to investigate the effect of combination therapy with an ERA and a sodium–glucose cotransporter 2 (SGLT2) inhibitor. Fluid retention and heart failure are important concerns with ERA use, but careful patient selection, dose optimization and use in combination with SGLT2 inhibitor therapy might mitigate these risks while enhancing kidney protection.

Background Kidney involvement in non-Hodgkin lymphoma is well recognized and glomerulonephritis, when present, has been commonly reported to be associated with a membranoproliferative pattern. Case presentation We report a case of a 58-year-old lady with a recurrence of non-Hodgkin MALT B-cell lymphoma, presenting with acute kidney injury, nephrotic range proteinuria and a cellular urinalysis. She underwent a renal biopsy that showed a severe diffuse proliferative and exudative lupus-like glomerulonephritis, which is likely paraneoplastic in nature. We discuss the differential diagnosis and possible pathogenesis of glomerular injury in lymphoma-related proliferative glomerulonephritis. Conclusion Differentiating between true lupus nephritis and a paraneoplastic glomerulonephritis is important, as it would have significant implications on treatment and clinical course.

Although low back pain (LBP) beliefs have been well investigated in mainstream healthcare discipline students, the beliefs within sports-related study students, such as Sport and Exercise Science (SES), Sports Therapy (ST), and Sport Performance and Coaching (SPC) programmes have yet to be explored. This study aims to understand any differences in the beliefs and fear associated with movement in students enrolled in four undergraduate study programmes-physiotherapy (PT), ST, SES, and SPC. 136 undergraduate students completed an online survey. All participants completed the Tampa Scale of Kinesiophobia (TSK) and Back Beliefs Questionnaire (BBQ). Two sets of two-way between-subjects Analysis of Variance (ANOVA) were conducted for each outcome of TSK and BBQ, with the independent variables of the study programme, study year (1st, 2nd, 3rd), and their interaction. There was a significant interaction between study programme and year for TSK (F(6, 124) = 4.90, P < 0.001) and BBQ (F(6, 124) = 8.18, P < 0.001). Post-hoc analysis revealed that both PT and ST students had lower TSK and higher BBQ scores than SES and SPC students particularly in the 3rd year. The beliefs of clinicians and trainers managing LBP are known to transfer to patients, and more negative beliefs have been associated with greater disability. This is the first study to understand the beliefs about back pain in various sports study programmes, which is timely, given that the management of injured athletes typically involves a multidisciplinary team.

Background Animal and plant genomes produce numerous small RNAs (smRNAs) that regulate gene expression post-transcriptionally affecting metabolism, development, and epigenetic inheritance. In order to characterize the repertoire of endogenous smRNAs and potential gene targets in dinoflagellates, we conducted smRNA and mRNA expression profiling over 9 experimental treatments of cultures from Symbiodinium microadriaticum , a photosynthetic symbiont of scleractinian corals. Results We identified a set of 21 novel smRNAs that share stringent key features with functional microRNAs from other model organisms. smRNAs were predicted independently over all 9 treatments and their putative gene targets were identified. We found 1,720 animal-like target sites in the 3'UTRs of 12,858 mRNAs and 19 plant-like target sites in 51,917 genes. We assembled a transcriptome of 58,649 genes and determined differentially expressed genes (DEGs) between treatments. Heat stress was found to produce a much larger number of DEGs than other treatments that yielded only few DEGs. Analysis of DEGs also revealed that minicircle-encoded photosynthesis proteins seem to be common targets of transcriptional regulation. Furthermore, we identified the core RNAi protein machinery in Symbiodinium . Conclusions Integration of smRNA and mRNA expression profiling identified a variety of processes that could be under microRNA control, e.g. protein modification, signaling, gene expression, and response to DNA damage. Given that Symbiodinium seems to have a paucity of transcription factors and differentially expressed genes, identification and characterization of its smRNA repertoire establishes the possibility of a range of gene regulatory mechanisms in dinoflagellates acting post-transcriptionally.