-
Advanced Science (Weinheim,... Sep 2023Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent...
Renal fibrosis is a common characteristic of various chronic kidney diseases (CKDs) driving the loss of renal function. During this pathological process, persistent injury to renal tubular epithelial cells and activation of fibroblasts chiefly determine the extent of renal fibrosis. In this study, the role of tumor protein 53 regulating kinase (TP53RK) in the pathogenesis of renal fibrosis and its underlying mechanisms is investigated. TP53RK is upregulated in fibrotic human and animal kidneys with a positive correlation to kidney dysfunction and fibrotic markers. Interestingly, specific deletion of TP53RK either in renal tubule or in fibroblasts in mice can mitigate renal fibrosis in CKD models. Mechanistic investigations reveal that TP53RK phosphorylates baculoviral IAP repeat containing 5 (Birc5) and facilitates its nuclear translocation; enhanced Birc5 displays a profibrotic effect possibly via activating PI3K/Akt and MAPK pathways. Moreover, pharmacologically inhibiting TP53RK and Birc5 using fusidic acid (an FDA-approved antibiotic) and YM-155(currently in clinical phase 2 trials) respectively both ameliorate kidney fibrosis. These findings demonstrate that activated TP53RK/Birc5 signaling in renal tubular cells and fibroblasts alters cellular phenotypes and drives CKD progression. A genetic or pharmacological blockade of this axis serves as a potential strategy for treating CKDs.
Topics: Animals; Humans; Mice; Fibrosis; Neoplasms; Phosphatidylinositol 3-Kinases; Protein Kinases; Renal Insufficiency, Chronic
PubMed: 37382161
DOI: 10.1002/advs.202301753 -
Kidney International Jul 2024Frailty is a condition that is frequently observed among patients undergoing dialysis. Frailty is characterized by a decline in both physiological state and cognitive... (Review)
Review
Frailty is a condition that is frequently observed among patients undergoing dialysis. Frailty is characterized by a decline in both physiological state and cognitive state, leading to a combination of symptoms, such as weight loss, exhaustion, low physical activity level, weakness, and slow walking speed. Frail patients not only experience a poor quality of life, but also are at higher risk of hospitalization, infection, cardiovascular events, dialysis-associated complications, and death. Frailty occurs as a result of a combination and interaction of various medical issues in patients who are on dialysis. Unfortunately, frailty has no cure. To address frailty, a multifaceted approach is necessary, involving coordinated efforts from nephrologists, geriatricians, nurses, allied health practitioners, and family members. Strategies such as optimizing nutrition and chronic kidney disease-related complications, reducing polypharmacy by deprescription, personalizing dialysis prescription, and considering home-based or assisted dialysis may help slow the decline of physical function over time in subjects with frailty. This review discusses the underlying causes of frailty in patients on dialysis and examines the methods and difficulties involved in managing frailty among this group.
Topics: Humans; Frailty; Renal Dialysis; Quality of Life; Aged; Frail Elderly; Polypharmacy; Geriatric Assessment; Risk Factors; Kidney Failure, Chronic; Renal Insufficiency, Chronic
PubMed: 38705274
DOI: 10.1016/j.kint.2024.02.026 -
Nefrologia 2024Receptor interacting protein kinase 3 (RIPK3) is an intracellular kinase at the crossroads of cell death and inflammation. RIPK3 contains a RIP homotypic interaction... (Review)
Review
Receptor interacting protein kinase 3 (RIPK3) is an intracellular kinase at the crossroads of cell death and inflammation. RIPK3 contains a RIP homotypic interaction motif (RHIM) domain which allows interactions with other RHIM-containing proteins and a kinase domain that allows phosphorylation of target proteins. RIPK3 may be activated through interaction with RHIM-containing proteins such as RIPK1, TRIF and DAI (ZBP1, DLM-1) or through RHIM-independent mechanisms in an alkaline intracellular pH. RIPK3 mediates necroptosis and promotes inflammation, independently of necroptosis, through either activation of NFκB or the inflammasome. There is in vivo preclinical evidence of the contribution of RIPK3 to both acute kidney injury (AKI) and chronic kidney disease (CKD) and to the AKI-to-CKD transition derived from RIPK3 deficient mice or the use of small molecule RIPK3 inhibitors. In these studies, RIPK3 targeting decreased inflammation but kidney injury improved only in some contexts. Clinical translation of these findings has been delayed by the potential of some small molecule inhibitors of RIPK3 kinase activity to trigger apoptotic cell death by inducing conformational changes of the protein. A better understanding of the conformational changes in RIPK3 that trigger apoptosis, dual RIPK3/RIPK1 inhibitors or repurposing of multiple kinase inhibitors such as dabrafenib may facilitate clinical development of the RIPK3 inhibition concept for diverse inflammatory diseases, including kidney diseases.
Topics: Animals; Mice; Apoptosis; Phosphorylation; Inflammation; Acute Kidney Injury; Renal Insufficiency, Chronic
PubMed: 37150671
DOI: 10.1016/j.nefroe.2023.04.006 -
CMAJ : Canadian Medical Association... Jul 2023
Review
Topics: Humans; Aged; Kidney Failure, Chronic; Renal Insufficiency, Chronic
PubMed: 37460121
DOI: 10.1503/cmaj.221427-f -
International Journal of Molecular... Nov 2023After acute kidney injury (AKI), renal function continues to deteriorate in some patients. In a pro-inflammatory and profibrotic environment, the proximal tubules are... (Review)
Review
After acute kidney injury (AKI), renal function continues to deteriorate in some patients. In a pro-inflammatory and profibrotic environment, the proximal tubules are subject to maladaptive repair. In the AKI-to-CKD transition, impaired recovery from AKI reduces tubular and glomerular filtration and leads to chronic kidney disease (CKD). Reduced kidney secretion capacity is characterized by the plasma accumulation of biologically active molecules, referred to as uremic toxins (UTs). These toxins have a role in the development of neurological, cardiovascular, bone, and renal complications of CKD. However, UTs might also cause CKD as well as be the consequence. Recent studies have shown that these molecules accumulate early in AKI and contribute to the establishment of this pro-inflammatory and profibrotic environment in the kidney. The objective of the present work was to review the mechanisms of UT toxicity that potentially contribute to the AKI-to-CKD transition in each renal compartment.
Topics: Humans; Uremic Toxins; Renal Insufficiency, Chronic; Kidney; Acute Kidney Injury; Toxins, Biological
PubMed: 38003343
DOI: 10.3390/ijms242216152 -
Diabetes, Obesity & Metabolism Nov 2023To estimate the lifetime benefit of a combination treatment of sodium-glucose co-transporter 2 (SGLT2) inhibitors and mineralocorticoid-receptor antagonists (MRA) in... (Observational Study)
Observational Study
Estimated lifetime benefit of novel pharmacological therapies in patients with type 2 diabetes and chronic kidney disease: A joint analysis of randomized controlled clinical trials.
AIM
To estimate the lifetime benefit of a combination treatment of sodium-glucose co-transporter 2 (SGLT2) inhibitors and mineralocorticoid-receptor antagonists (MRA) in patients with type 2 diabetes and chronic kidney disease (CKD).
MATERIALS AND METHODS
The cumulative effect of combination treatment was derived from trial-level estimates of the effect of an SGLT2 inhibitor (canagliflozin) and MRA (finerenone) from the CREDENCE (N = 4401) and FIDELIO (N = 5734) trials, respectively. The cumulative effect was applied to the control group of patients with type 2 diabetes in the DAPA-CKD trial (N = 1451) to estimate long-term gains in event-free and overall survival. The analysis was repeated in an observational study. The primary outcome was a composite endpoint of doubling of serum creatinine, end-stage kidney disease or death because of kidney failure.
RESULTS
The hazard ratio of combination treatment for the primary outcome was 0.50 [95% confidence interval (CI): 0.44, 0.57]. At age 50 years, the estimated event-free survival from the primary outcome was 16.7 years (95% CI: 18.1, 21.0) with combination treatment versus 10.0 years (95% CI: 6.8, 12.3) with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers resulting in an incremental gain of 6.7 years (95% CI: 5.5, 7.9). In an observational study, the estimated gain in event-free survival regarding primary outcome was 6.3 years (95% CI: 5.2, 7.3). In a conservative scenario, assuming low adherence (70% of the observed adherence) and less pronounced efficacy (70% of the observed efficacy with 2% yearly decline) of combination therapy, gain in event-free survival regarding primary outcome was 2.5 years (95% CI: 2.0, 2.9).
CONCLUSIONS
Combined disease-modifying treatment with an SGLT2 inhibitor and MRA in patients with type 2 diabetes and CKD may substantially increase the number of years free from kidney failure and mortality.
Topics: Humans; Middle Aged; Diabetes Mellitus, Type 2; Sodium-Glucose Transporter 2 Inhibitors; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Canagliflozin; Mineralocorticoid Receptor Antagonists
PubMed: 37580309
DOI: 10.1111/dom.15232 -
Biomedical Journal Aug 2023Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute,... (Review)
Review
Leptospirosis is a neglected bacterial disease caused by leptospiral infection that carries a substantial mortality risk in severe cases. Research has shown that acute, chronic, and asymptomatic leptospiral infections are closely linked to acute and chronic kidney disease (CKD) and renal fibrosis. Leptospires affect renal function by infiltrating kidney cells via the renal tubules and interstitium and surviving in the kidney by circumventing the immune system. The most well-known pathogenic molecular mechanism of renal tubular damage caused by leptospiral infection is the direct binding of the bacterial outer membrane protein LipL32 to toll-like receptor-2 expressed in renal tubular epithelial cells (TECs) to induce intracellular inflammatory signaling pathways. These pathways include the production of tumor necrosis factor (TNF)-α and nuclear factor kappa activation, resulting in acute and chronic leptospirosis-related kidney injury. Few studies have investigated the relationship between acute and chronic renal diseases and leptospirosis and further evidence is necessary. In this review, we intend to discuss the roles of acute kidney injury (AKI) to/on CKD in leptospirosis. This study reviews the molecular pathways underlying the pathogenesis of leptospirosis kidney disease, which will assist in concentrating on potential future research directions.
Topics: Humans; Leptospirosis; Renal Insufficiency, Chronic; Kidney; Leptospira; Acute Kidney Injury
PubMed: 37142093
DOI: 10.1016/j.bj.2023.100595 -
International Journal of Molecular... Dec 2023This review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of... (Review)
Review
This review examines the impact of childhood obesity on the kidney from an epidemiological, pathogenetic, clinical, and pathological perspective, with the aim of providing pediatricians and nephrologists with the most current data on this topic. The prevalence of childhood obesity and chronic kidney disease (CKD) is steadily increasing worldwide, reaching epidemic proportions. While the impact of obesity in children with CKD is less pronounced than in adults, recent studies suggest a similar trend in the child population. This is likely due to the significant association between obesity and the two leading causes of end-stage renal disease (ESRD): diabetes mellitus (DM) and hypertension. Obesity is a complex, systemic disease that reflects interactions between environmental and genetic factors. A key mechanism of kidney damage is related to metabolic syndrome and insulin resistance. Therefore, we can speculate about an adipose tissue-kidney axis in which neurohormonal and immunological mechanisms exacerbate complications resulting from obesity. Adipose tissue, now recognized as an endocrine organ, secretes cytokines called adipokines that may induce adaptive or maladaptive responses in renal cells, leading to kidney fibrosis. The impact of obesity on kidney transplant-related outcomes for both donors and recipients is also significant, making stringent preventive measures critical in the pre- and post-transplant phases. The challenge lies in identifying renal involvement as early as possible, as it is often completely asymptomatic and not detectable through common markers of kidney function. Ongoing research into innovative technologies, such as proteomics and metabolomics, aims to identify new biomarkers and is constantly evolving. Many aspects of pediatric disease progression in the population of children with obesity still require clarification. However, the latest scientific evidence in the field of nephrology offers glimpses into various new perspectives, such as genetic factors, comorbidities, and novel biomarkers. Investigating these aspects early could potentially improve the prognosis of these young patients through new diagnostic and therapeutic strategies. Hence, the aim of this review is to provide a comprehensive exploration of the pathogenetic mechanisms and prevalent pathological patterns of kidney damage observed in children with obesity.
Topics: Adult; Humans; Child; Pediatric Obesity; Kidney; Renal Insufficiency, Chronic; Kidney Failure, Chronic; Biomarkers
PubMed: 38139229
DOI: 10.3390/ijms242417400 -
British Journal of Hospital Medicine... Jul 2023Inherited kidney disease accounts for a significant proportion of chronic kidney disease and end-stage renal failure. There is increasing evidence that genetic testing... (Review)
Review
Inherited kidney disease accounts for a significant proportion of chronic kidney disease and end-stage renal failure. There is increasing evidence that genetic testing for inherited kidney disease should be integrated into clinical care pathways at the earliest opportunity so that patients and their families can maximally benefit from carefully tailored care. Despite increased availability of genetic testing, the proportion of patients with renal disease undergoing genetic investigations remains low. This article introduces key concepts of genetic and genomic testing to the renal physician and addresses some common barriers to the wider integration of genetic testing in routine clinical practice to fully capitalise on recent advances in genomic medicine and improve patient outcomes.
Topics: Humans; Kidney; Genetic Testing; Kidney Failure, Chronic; Renal Insufficiency, Chronic; Genomics
PubMed: 37490441
DOI: 10.12968/hmed.2023.0085 -
International Journal of Biological... 2023High-mobility group protein box 1 (HMGB1) is a member of a highly conserved high-mobility group protein present in all cell types. HMGB1 plays multiple roles both inside... (Review)
Review
High-mobility group protein box 1 (HMGB1) is a member of a highly conserved high-mobility group protein present in all cell types. HMGB1 plays multiple roles both inside and outside the cell, depending on its subcellular localization, context, and post-translational modifications. HMGB1 is also associated with the progression of various diseases. Particularly, HMGB1 plays a critical role in CKD progression and prognosis. HMGB1 participates in multiple key events in CKD progression by activating downstream signals, including renal inflammation, the onset of persistent fibrosis, renal aging, AKI-to-CKD transition, and important cardiovascular complications. More importantly, HMGB1 plays a distinct role in the chronic pathophysiology of kidney disease, which differs from that in acute lesions. This review describes the regulatory role of HMGB1 in renal homeostasis and summarizes how HMGB1 affects CKD progression and prognosis. Finally, some promising therapeutic strategies for the targeted inhibition of HMGB1 in improving CKD are summarized. Although the application of HMGB1 as a therapeutic target in CKD faces some challenges, a more in-depth understanding of the intracellular and extracellular regulatory mechanisms of HMGB1 that underly the occurrence and progression of CKD might render HMGB1 an attractive therapeutic target for CKD.
Topics: Humans; HMGB1 Protein; Acute Kidney Injury; Renal Insufficiency, Chronic; Kidney; Aging; Disease Progression
PubMed: 37781525
DOI: 10.7150/ijbs.87964