Efficacy and safety of hypoxia-inducible factor prolyl hydroxylase inhibitors in patients with chronic kidney disease: meta-analysis of phase 3 randomized controlled trials.

Background: Hypoxia-inducible factor prolyl hydroxylase inhibitors (HIF-PHIs) are new therapeutic agents for anaemia in chronic kidney disease (CKD). We evaluated by meta-analysis and meta-regression the efficacy and safety of HIF-PHIs in patients with CKD-related anaemia.

Methods: We selected phase 3 randomized clinical trials (RCTs) comparing HIF-PHIs and erythropoiesis-stimulating agents (ESAs) in dialysis and non-dialysis patients.

Secular Trend in GFR Decline in Non-Dialysis CKD Based on Observational Data From Standard of Care Arms of Trials.

Rationale & Objective: The standard of care (SoC) group of randomized controlled trials (RCTs) is a useful setting to explore the secular trends in kidney disease progression because implementation of best clinical practices is pursued for all patients enrolled in trials. This meta-analysis evaluated the secular trend in the change of glomerular filtration rate (GFR) decline in the SoC arm of RCTs in chronic kidney disease (CKD) published in the last 30 years.

Study Design: Systematic review and meta-analysis of the SoC arms of RCTs analyzed as an observational study.

Assessment of pharmacokinetics, safety, and tolerability following twice-daily administration of molnupiravir for 10 days in healthy participants.

Molnupiravir is an orally administered, small-molecule ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) that has demonstrated potent, broad-spectrum preclinical activity against RNA viruses and has a high barrier to the development of resistance. A double-blind, placebo-controlled, phase I trial was conducted to evaluate the pharmacokinetics (PKs), safety, and tolerability of 10.5-day administration of multiple doses of molnupiravir and its metabolites in healthy, adult participants.

Sustained Recovery of Kidney Function in Patients with ESKD under Chronic Dialysis Treatment: Systematic Review and Meta-Analysis.

The prevalence of recovery of kidney function (RKF) in patients under maintenance dialysis is poorly defined mainly because of different definitions of RKF. Therefore, to gain more insights into the epidemiology of RKF, we performed a systematic review and meta-analysis of studies addressing the prevalence of sustained (at least for 30 days) RKF in patients under maintenance dialysis. Acute kidney injury (AKI) and RKF in the first 90 days of dialysis were the main exclusion criteria.

Arginine limitation causes a directed DNA sequence evolution response in colorectal cancer cells.

Utilization of specific codons varies significantly across organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons.

Arginine limitation drives a directed codon-dependent DNA sequence evolution response in colorectal cancer cells.

Utilization of specific codons varies between organisms. Cancer represents a model for understanding DNA sequence evolution and could reveal causal factors underlying codon evolution. We found that across human cancer, arginine codons are frequently mutated to other codons.

Dipping Status, Ambulatory Blood Pressure Control, Cardiovascular Disease, and Kidney Disease Progression: A Multicenter Cohort Study of CKD.

Rationale & Objective: Ambulatory blood pressure (BP) monitoring allows concurrent evaluation of BP control and nocturnal BP dipping status, both related to adverse outcomes. However, few studies have assessed the prognostic role of combining information on dipping status and achieved ambulatory BP in patients with chronic kidney disease (CKD).

Study Design: Prospective observational cohort study.

New-onset anemia and associated risk of ESKD and death in non-dialysis CKD patients: a multicohort observational study.

Background: Anemia is a common complication of chronic kidney disease (CKD), but its incidence in nephrology settings is poorly investigated. Similarly, the risks of adverse outcomes associated with new-onset anemia are not known.

Methods: We performed a pooled analysis of three observational cohort studies including 1031 non-anemic CKD patients with eGFR <60 mL/min/1.

Leucyl-tRNA synthetase is a tumour suppressor in breast cancer and regulates codon-dependent translation dynamics.

Tumourigenesis and cancer progression require enhanced global protein translation. Such enhanced translation is caused by oncogenic and tumour-suppressive events that drive the synthesis and activity of translational machinery. Here we report the surprising observation that leucyl-tRNA synthetase (LARS) becomes repressed during mammary cell transformation and in human breast cancer.

Ferric Carboxymatose in Non-Hemodialysis CKD Patients: A Longitudinal Cohort Study.

No information is available on the efficacy of ferric carboxymaltose (FCM) in real-world CKD patients outside the hemodialysis setting. We prospectively followed 59 non-hemodialysis CKD patients with iron deficient anemia (IDA: hemoglobin <12.0/<13.

Sodium Intake and Chronic Kidney Disease.

In Chronic Kidney Disease (CKD) patients, elevated blood pressure (BP) is a frequent finding and is traditionally considered a direct consequence of their sodium sensitivity. Indeed, sodium and fluid retention, causing hypervolemia, leads to the development of hypertension in CKD. On the other hand, in non-dialysis CKD patients, salt restriction reduces BP levels and enhances anti-proteinuric effect of renin-angiotensin-aldosterone system inhibitors in non-dialysis CKD patients.

Histone Lactylation: A New Role for Glucose Metabolism.

Lactate is an end product of glucose metabolism, which serves metabolic and nonmetabolic functions. A new study by Zhang et al. establishes a novel function for lactate whereby it is utilized in a new histone modification, histone lysine lactylation, to regulate gene expression in macrophages.

PCK1 and DHODH drive colorectal cancer liver metastatic colonization and hypoxic growth by promoting nucleotide synthesis.

Colorectal cancer (CRC) is a major cause of human death. Mortality is primarily due to metastatic organ colonization, with the liver being the main organ affected. We modeled metastatic CRC (mCRC) liver colonization using patient-derived primary and metastatic tumor xenografts (PDX).

Evolved resistance to partial GAPDH inhibition results in loss of the Warburg effect and in a different state of glycolysis.

Aerobic glycolysis or the Warburg effect (WE) is characterized by increased glucose uptake and incomplete oxidation to lactate. Although the WE is ubiquitous, its biological role remains controversial, and whether glucose metabolism is functionally different during fully oxidative glycolysis or during the WE is unknown. To investigate this question, here we evolved resistance to koningic acid (KA), a natural product that specifically inhibits glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a rate-controlling glycolytic enzyme, during the WE.

Discovery of a Potent GLUT Inhibitor from a Library of Rapafucins by Using 3D Microarrays.

Glucose transporters play an essential role in cancer cell proliferation and survival and have been pursued as promising cancer drug targets. Using microarrays of a library of new macrocycles known as rapafucins, which were inspired by the natural product rapamycin, we screened for new inhibitors of GLUT1. We identified multiple hits from the rapafucin 3D microarray and confirmed one hit as a bona fide GLUT1 ligand, which we named rapaglutin A (RgA).

SGLT2 Inhibitors: Nephroprotective Efficacy and Side Effects.

The burden of diabetic kidney disease (DKD) has increased worldwide in the last two decades. Besides the growth of diabetic population, the main contributors to this phenomenon are the absence of novel nephroprotective drugs and the limited efficacy of those currently available, that is, the inhibitors of renin-angiotensin system. Nephroprotection in DKD therefore remains a major unmet need.

Serine synthesis through PHGDH coordinates nucleotide levels by maintaining central carbon metabolism.

Phosphoglycerate dehydrogenase (PHGDH) catalyzes the committed step in de novo serine biosynthesis. Paradoxically, PHGDH and serine synthesis are required in the presence of abundant environmental serine even when serine uptake exceeds the requirements for nucleotide synthesis. Here, we establish a mechanism for how PHGDH maintains nucleotide metabolism.

Distinct Regulation of Th17 and Th1 Cell Differentiation by Glutaminase-Dependent Metabolism.

Activated T cells differentiate into functional subsets with distinct metabolic programs. Glutaminase (GLS) converts glutamine to glutamate to support the tricarboxylic acid cycle and redox and epigenetic reactions. Here, we identify a key role for GLS in T cell activation and specification.

High-flow arteriovenous fistula and heart failure: could the indexation of blood flow rate and echocardiography have a role in the identification of patients at higher risk?

Background: Although only high-flow arteriovenous fistulas (AVFs) are postulated to cause high-output cardiac failure (HOCF), there are currently no universally accepted criteria defining a high-flow fistula.

Methods: To verify if vascular access blood flow (Qa) ≥ 2000 ml/min provides an accurate definition of high-flow fistula, we selected 29 consecutive patients with Qa ≥ 2000 ml/min at color-duplex ultrasound examination and assessed them for the presence of cardiac failure symptoms; transthoracic echocardiography was also performed.

Results: Nineteen patients (65%) had heart failure symptoms and were classified with HOCF.

Melanoma Therapeutic Strategies that Select against Resistance by Exploiting MYC-Driven Evolutionary Convergence.

Diverse pathways drive resistance to BRAF/MEK inhibitors in BRAF-mutant melanoma, suggesting that durable control of resistance will be a challenge. By combining statistical modeling of genomic data from matched pre-treatment and post-relapse patient tumors with functional interrogation of >20 in vitro and in vivo resistance models, we discovered that major pathways of resistance converge to activate the transcription factor, c-MYC (MYC). MYC expression and pathway gene signatures were suppressed following drug treatment, and then rebounded during progression.