Kidney International

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Chan et al. conducted a post hoc analysis of the Study of Diabetic Nephropathy with Atrasentan (SONAR) to demonstrate that atrasentan reduced chronic pain-related adverse events reported by investigators and the initiation of analgesics. This study creates an interesting hypothesis, but it is limited in that the pain information was collected as part of the adverse events and the presence/absence of pain at baseline was unknown. Thus, prospective clinical trials are required to confirm these findings.

Proteomics has illuminated disease pathophysiology, unearthed novel biomarkers, and bolstered risk assessment strategies. In nephrology, observational analyses unveil biomarkers associated with adverse outcomes, whereas genetics offer insights into causal pathways. Mendelian randomization offers the potential to link the two, uncovering causal relationships between biomarkers and kidney function. Lanktree et al. demonstrate Mendelian randomization's utility in identifying additional proteins affecting kidney function and kidney disease progression...

The presence of glycolysis in kidney proximal tubule has been long debated. However, recent reports suggest that aberrant glycolysis is induced in pathologic conditions and may play a critical role in kidney damage. Azushima et al. provided additional evidence that the accumulation of glycolysis-derived lactate could be the clue to understanding the pathogenesis of diabetic kidney disease.

Anti-glomerular basement membrane (anti-GBM) disease is typically characterized by autoimmunity against the α3 chain of type IV collagen. Rarely, circulating autoantibodies are not detected. These atypical cases follow a more indolent clinical course, and underlying mechanisms, including alternative target antigens, require investigation. In this issue of Kidney International, Kuang et al. describe a case of anti-GBM disease with autoantibodies against the GBM component laminin-521 and demonstrate that laminin-521 is pathogenic in a rat model of anti-GBM glomerulonephritis...

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The efficient reabsorption of essential nutrients by epithelial cells in the proximal tubule of the kidney is crucial for maintaining homeostasis. This process relies heavily on a complex ecosystem of vesicular trafficking pathways. At the center of this network, the lysosome plays a pivotal role in processing incoming molecules, sensing nutrient availability, sorting receptors and transporters, and balancing differentiation and proliferation in the tubular epithelial cells. Disruptions in these fundamental processes can lead to proximal tubulopathy-a condition characterized by the dysfunction of the tubular cells followed by the presence of low-molecular-weight proteins and solutes in urine...

Estimated glomerular filtration rate (eGFR) impacts the concentration of plasma biomarkers confounding biomarker association studies of eGFR with reverse causation. To identify biomarkers causally associated with eGFR, we performed a proteome-wide Mendelian randomization study. Genetic variants nearby biomarker coding genes were tested for association with plasma concentration of 1,161 biomarkers in a multi-ancestry sample of 12,066 participants from the Prospective Urban and Rural Epidemiological (PURE) study...

Accurate estimation of chronic kidney disease (CKD) progression risk is vital for clinical decision-making. Existing risk equations lack validation in pediatric CKD populations. Ng et al. developed new risk equations using the CKD in Children and European Study Consortium for Chronic Kidney Disorders Affecting Pediatric Patients cohorts. The elementary model, incorporating estimated glomerular filtration rate, urine protein-creatinine ratio, and diagnosis, exhibited excellent discrimination and calibration at external validation...

Urinary stone disease is based on gene-environment interaction with an almost 50% heritability. Despite all efforts from exome-sequencing and genome-wide association studies, the genetic factors making up for observed heritability have been incompletely characterized. The study by Sadeghi-Alavijeh et al. leverages the invaluable resources of the 100,000 Genomes Project and the UK Biobank to identify heterozygous rare variants in the phosphate transporter SLC34A3 as a significant factor of urinary stone disease, challenging the traditional concept of Mendelian inheritance...

Matrix metalloproteinases (MMPs) cleave matrix components along with multiple other effects. They are integral to virtually all biological processes, including inflammation and wound healing. As such, MMPs have been studied in the context of peritoneal membrane injury. MMP10 is a stromelysin and is involved in the degradation of matrix proteoglycans. Ishimura et al. demonstrate that MMP10 is involved in peritoneal membrane fibrosis. The clinical implications of these observations are presently unknown.

Much akin to the explosion in number of known target antigens in membranous nephropathy, there has been a rapid expansion in the availability of animal models involving the first 2 antigens discovered in adult disease, phospholipase A2 receptor and thrombospondin type 1 domain-containing 7A. In this issue, Tomas et al. describe a novel mouse model of phospholipase A2 receptor-associated membranous nephropathy that shows great promise for investigating molecular mechanisms of disease and as an experimental system for testing existing and emerging therapies...

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