Identification and study of new NF-κB-inducing kinase ligands derived from the imidazolone scaffold.

Chronic kidney disease (CKD) is a growing health concern, projected to be a major cause of death by 2040, due to an increasing risk of acute kidney injury (AKI). Systems biology-derived data suggest that the unmet need for an orally available drug to treat AKI and improve CKD outcomes may be addressed by targeting kidney inflammation and, specifically, nuclear factor κB-inducing kinase (NIK), a key signaling molecule that activates the noncanonical nuclear factor κB (NF-κB) pathway. We have prepared and identified a small family of imidazolone derivatives that bind NIK and inhibit the noncanonical NF-κB activation pathway.

Cefadroxil Targeting of SLC15A2/PEPT2 Protects From Colistin Nephrotoxicity.

Acute kidney injury (AKI) and chronic kidney disease (CKD) are considered interconnected syndromes, as AKI episodes may accelerate CKD progression, and CKD increases the risk of AKI. Genome-wide association studies (GWAS) may identify novel actionable therapeutic targets. Human GWAS for AKI or CKD were combined with murine AKI transcriptomics data sets to identify 13 (ACACB, ACSM5, CNDP1, DPEP1, GATM, SLC6A12, AGXT2L1, SLC15A2, CTSS, ICAM1, ITGAX, ITGAM, and PPM1J) potentially actionable therapeutic targets to modulate kidney disease severity across species and the AKI-CKD spectrum.

NIK Is a Mediator of Inflammation and Intimal Hyperplasia in Endothelial Denudation-Induced Vascular Injury.

Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. NFκB is a key mediator of inflammation that is activated during neointimal hyperplasia following endothelial injury. However, the molecular mechanisms involved in NFκB activation are poorly understood.

Paricalcitol Has a Potent Anti-Inflammatory Effect in Rat Endothelial Denudation-Induced Intimal Hyperplasia.

Neointimal hyperplasia is the main cause of vascular graft failure in the medium term. Vitamin D receptor activation modulates the biology of vascular smooth muscle cells and has been reported to protect from neointimal hyperplasia following endothelial injury. However, the molecular mechanisms are poorly understood.

Increased expression of SCARF genes favoring SARS-CoV-2 infection in key target organs in CKD.

Background: Chronic kidney disease (CKD), especially diabetic CKD, is the condition that most increases the risk of lethal coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, the underlying molecular mechanisms are unclear. SARS-CoV-2 and coronavirus-associated receptors and factors (SCARFs) regulate coronavirus cell entry and/or replication.

SCARF Genes in COVID-19 and Kidney Disease: A Path to Comorbidity-Specific Therapies.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), which has killed ~7 million persons worldwide. Chronic kidney disease (CKD) is the most common risk factor for severe COVID-19 and one that most increases the risk of COVID-19-related death. Moreover, CKD increases the risk of acute kidney injury (AKI), and COVID-19 patients with AKI are at an increased risk of death.

NephroCheck at 10: addressing unmet needs in AKI diagnosis and risk stratification.

Despite its name, the current diagnosis of acute kidney injury (AKI) still depends on markers of decreased kidney function and not on markers of injury. This results in a delayed diagnosis: AKI is diagnosed based on serum creatinine criteria only when the severity of injury is enough to decrease glomerular filtration rate. Moreover, by the time AKI is diagnosed, the insult may have already ceased, and even appropriate therapy targeted at the specific insult and its associated pathogenic pathways may no longer be effective.

Time-Dependent Changes of Klotho and FGF-23 Levels after Kidney Transplantation: Role of Cold Ischemia Time, Renal Function and Graft Inflammation.

We investigated the evolution of serum klotho (s-Kl) and FGF-23 during the first two years post-kidney transplantation (KT), considering the cold ischemia time (CIT), glomerular filtration rate (GFR) and graft subclinical inflammation (SCI). We undertook a prospective, cohort, multicenter study of consecutive patients between April 2018 and January 2021 (with follow-up at 24 months). Subgroups were analyzed according to the median CIT (<14 vs.

Regulated cell death pathways in kidney disease.

Disorders of cell number that result from an imbalance between the death of parenchymal cells and the proliferation or recruitment of maladaptive cells contributes to the pathogenesis of kidney disease. Acute kidney injury can result from an acute loss of kidney epithelial cells. In chronic kidney disease, loss of kidney epithelial cells leads to glomerulosclerosis and tubular atrophy, whereas interstitial inflammation and fibrosis result from an excess of leukocytes and myofibroblasts.

Sodium-glucose co-transporter-2 inhibitors increase Klotho in patients with diabetic kidney disease: A clinical and experimental study.

Sodium-glucose co-transporter-2 inhibitors (SGLT2i) provide cardiorenal protection. However, the molecular mechanisms remain poorly understood. We explored the impact of SGLT2i on Klotho, a kidney-derived protein with antiaging, renal-protective and heart-protective properties.

Sodium zirconium cyclosilicate and metabolic acidosis: Potential mechanisms and clinical consequences.

Metabolic acidosis is frequent in chronic kidney disease (CKD) and is associated with accelerated progression of CKD, hypercatabolism, bone disease, hyperkalemia, and mortality. Clinical guidelines recommend a target serum bicarbonate ≥ 22 mmol/L, but metabolic acidosis frequently remains undiagnosed and untreated. Sodium zirconium cyclosilicate (SZC) binds potassium in the gut and is approved to treat hyperkalemia.

Obesity, chronic kidney disease progression and the role of the adipokine C1q/TNF related protein-3.

Introduction And Aims: Obesity is a risk factor for incident chronic kidney disease (CKD). C1q/TNF related protein 3 (CTRP3) is an adipokine with multiple effects and may modulate the association between obesity and vascular diseases. The aim of the study is to explore potential links between obesity, CTRP3 levels and CKD progression.

Who killed Bruce Lee? The hyponatraemia hypothesis.

Bruce Lee brought attention to martial arts in the Western world and popularized the quote 'Be water, my friend'. Lee died at the age of 32 years in Hong Kong on 20 July 1973, under mysterious circumstances. The cause of death is unknown, although numerous hypotheses have been proposed, from assassination by gangsters to the more recent suggestion in 2018 that he died from heatstroke.

Repurposing drugs for highly prevalent diseases: pentoxifylline, an old drug and a new opportunity for diabetic kidney disease.

Diabetic kidney disease is one of the most frequent complications in patients with diabetes and constitutes a major cause of end-stage kidney disease. The prevalence of diabetic kidney disease continues to increase as a result of the growing epidemic of diabetes and obesity. Therefore, there is mounting urgency to design and optimize novel strategies and drugs that delay the progression of this pathology and contain this trend.

Postbiotics and Kidney Disease.

Chronic kidney disease (CKD) is projected to become the fifth global cause of death by 2040 as a result of key shortcomings in the current methods available to diagnose and treat kidney diseases. In this regard, the novel holobiont concept, used to describe an individual host and its microbial community, may pave the way towards a better understanding of kidney disease pathogenesis and progression. Microbiota-modulating or -derived interventions include probiotics, prebiotics, synbiotics and postbiotics.

Solving the riddle of Aguascalientes nephropathy: nephron number, environmental toxins and family clustering.

Aguascalientes, Mexico, has a high incidence and prevalence of advanced chronic kidney disease (CKD). CKD is especially frequent in young people ages 20-40 years in whom the cause of CKD was unknown, although kidney biopsies frequently showed focal segmental glomerulosclerosis (FSGS) and glomerulomegaly. Macias-Diaz .

Growth differentiation factor-15 preserves Klotho expression in acute kidney injury and kidney fibrosis.

Growth differentiation factor-15 (GDF15) is a member of the GDF subfamily with potential kidney protective functions. Here, we explored the impact of GDF15 on the expression of the kidney protective factor Klotho in models of acute kidney injury and kidney fibrosis in mice. GDF15 was the most upregulated GDF family gene in experimental toxic acute kidney injury and in kidney fibrosis transcriptomics.

Growth Differentiation Factor-15 and Syndecan-1 Are Potential Biomarkers of Cardiac and Renal Involvement in Classical Fabry Disease under Enzyme Replacement Therapy.

Background And Aims: Inflammation and endothelial damage play a pivotal role in Fabry disease (FD) manifestations. In daily clinical practice, FD is mainly monitored by traditional biomarkers of target organ injury, such as serum creatinine and proteinuria, which provide no information about inflammation and endothelial damage.

Materials And Methods: We investigated the serum levels of 3-nitrotyrosine (3-NT), an oxidative stress biomarker, and of growth differentiation factor-15 (GDF-15) and syndecan-1 in classical FD patients on enzyme replacement therapy (ERT) for at least 6 months and their relationship with Fabry-related cardiac and renal manifestations.

Phosphate, Microbiota and CKD.

Phosphate is a key uremic toxin associated with adverse outcomes. As chronic kidney disease (CKD) progresses, the kidney capacity to excrete excess dietary phosphate decreases, triggering compensatory endocrine responses that drive CKD-mineral and bone disorder (CKD-MBD). Eventually, hyperphosphatemia develops, and low phosphate diet and phosphate binders are prescribed.

Urinary Growth Differentiation Factor-15 (GDF15) levels as a biomarker of adverse outcomes and biopsy findings in chronic kidney disease.

Background: Growth Differentiation Factor-15 (GDF15) is a member of the TGF-β superfamily. Increased serum GDF15 has been associated with increased risk of chronic kidney disease (CKD) progression. However, no prior studies have addressed the significance of urinary GDF15 in adult CKD.

Renin-angiotensin system and inflammation update.

The most classical view of the renin-angiotensin system (RAS) emphasizes its role as an endocrine regulator of sodium balance and blood pressure. However, it has long become clear that the RAS has pleiotropic actions that contribute to organ damage, including modulation of inflammation. Angiotensin II (Ang II) activates angiotensin type 1 receptors (AT1R) to promote an inflammatory response and organ damage.

Chloroquine may induce endothelial injury through lysosomal dysfunction and oxidative stress.

COVID-19 is a pandemic with no end in sight. There is only one approved antiviral agent but global stocks are deemed insufficient. Despite in vitro antiviral activity, clinical trials of chloroquine and hydroxychloroquine were disappointing, and they may even impair outcomes.

Lyso-Gb3 Increases αvβ3 Integrin Gene Expression in Cultured Human Podocytes in Fabry Nephropathy.

Background: Podocyturia in Fabry nephropathy leads to glomerulosclerosis and kidney disease progression. Integrins are involved in podocyte attachment to the glomerular basement membrane. We hypothesized that in Fabry nephropathy, lyso-Gb3 could modulate αvβ3 expression in podocytes.

Tacrolimus Prevents TWEAK-Induced PLA2R Expression in Cultured Human Podocytes.

Primary membranous nephropathy is usually caused by antibodies against the podocyte antigen membrane M-type phospholipase A2 receptor (PLA2R). The treatment of membranous nephropathy is not fully satisfactory. The calcineurin inhibitor tacrolimus is used to treat membranous nephropathy, but recurrence upon drug withdrawal is common.