Potential role of molecular hydrogen therapy on oxidative stress and redox signaling in chronic kidney disease.

Oxidative stress plays a key role in chronic kidney disease (CKD) development and progression, inducing kidney cell damage, inflammation, and fibrosis. However, effective therapeutic interventions to slow down CKD advancement are currently lacking. The multifaceted pharmacological effects of molecular hydrogen (H2) have made it a promising therapeutic avenue. H2 is capable of capturing harmful •OH and ONOO- while maintaining the crucial reactive oxygen species (ROS) involved in cellular signaling. The NRF2-KEAP1 system, which manages cell redox balance, could be used to treat CKD. H2 activates this pathway, fortifying antioxidant defenses and scavenging ROS to counteract oxidative stress. H2 can improve NRF2 signaling by using the Wnt/ß-catenin pathway and indirectly activate NRF2-KEAP1 in mitochondria. Additionally, H2 modulates NF-κB activity by regulating cellular redox status, inhibiting MAPK pathways, and maintaining Trx levels. Treatment with H2 also attenuates HIF signaling by neutralizing ROS while indirectly bolstering HIF-1α function. Furthermore, H2 affects FOXO factors and enhances the activity of antioxidant enzymes. Despite the encouraging results of bench studies, clinical trials are still limited and require further investigation. The focus of this review is on hydrogen's role in treating renal diseases, with a specific focus on oxidative stress and redox signaling regulation, and it discusses its potential clinical applications.

The Association between Diabetic Retinopathy and Macular Degeneration: A Nationwide Population-Based Study.

OBJECTIVE: Age-related macular degeneration (AMD), particularly its exudative form, is a primary cause of vision impairment in older adults. As diabetes becomes increasingly prevalent in aging, it is crucial to explore the potential relationship between diabetic retinopathy (DR) and AMD. This study aimed to assess the risk of developing overall, non-exudative, and exudative AMD in individuals with DR compared to those without retinopathy (non-DR) based on a nationwide population study in Taiwan. METHODS: A retrospective cohort study was conducted using the Taiwan National Health Insurance Database (NHIRD) (2000-2013). A total of 3413 patients were placed in the study group (DR) and 13,652 in the control group (non-DR) for analysis. Kaplan-Meier analysis and the Cox proportional hazards model were used to calculate the hazard ratios (HRs) and adjusted hazard ratios (aHRs) for the development of AMD, adjusting for confounding factors, such as age, sex, and comorbid conditions. RESULTS: Kaplan-Meier survival analysis indicated a significantly higher cumulative incidence of AMD in the DR group compared to the non-DR group (log-rank test, p < 0.001). Adjusted analyses revealed that individuals with DR faced a greater risk of overall AMD, with an aHR of 3.50 (95% CI = 3.10-3.95). For senile (unspecified) AMD, the aHR was 3.45 (95% CI = 3.04-3.92); for non-exudative senile AMD, it was 2.92 (95% CI = 2.08-4.09); and for exudative AMD, the aHR was 3.92 (95% CI = 2.51-6.14). CONCLUSION: DR is a significant risk factor for both overall, senile, exudative, and non-exudative AMD, even after adjusting for demographic and comorbid conditions. DR patients tend to have a higher prevalence of vascular comorbidities; however, our findings indicate that the ocular pathologies inherent to DR might have a more significant impact on the progression to AMD. Early detection and appropriate treatment of AMD is critically important among DR patients.

Polystyrene microplastic-induced extracellular vesicles cause kidney-related effects in the crosstalk between tubular cells and fibroblasts.

Plastic waste accumulation and its degradation into microplastics (MPs) and nanoplastics (NPs) pose environmental concerns. Previous studies have indicated that polystyrene (PS)-MPs harm living animals. Extracellular vesicles (EVs) are associated with metabolic reprogramming and mitochondrial dysfunction in various kidney diseases. In this article, we evaluated how PS-MPs affected tubular cells and fibroblasts. The results demonstrated that PS-MPs increased EV production in human tubular cells and caused endoplasmic reticulum (ER) stress-related proteins without inducing inflammation-related proteins in human tubular cells. The uptake of PS-MPs and incubation with the conditioned medium of PS-MPs induced reactive oxygen species (ROS) production and ER stress-related proteins in fibroblast cells. The fibroblast cells treated with the conditioned medium of PS-MPs also increased the expression of fibrosis-related proteins. Our findings suggested that the expression of EV-related markers increased in tubular cells via Beclin 1 after PS-MP treatment. In addition, PS-MPs induced ROS production in vitro and in vivo. We found that PS-MPs also altered the expression of EV markers in urine, and CD63 expression was also increased in vitro and in vivo after PS-MP treatment. In conclusion, PS-MP-induced EVs lead to ER stress-related proteins, ROS production and fibrosis-related proteins in tubular cells and fibroblasts.

The influence of uremic toxins on low bone turnover disease in chronic kidney disease.

Uremic toxins play a crucial role in the development of low bone turnover disease in chronic kidney disease (CKD) through the induction of oxidative stress. This oxidative stress disrupts the delicate balance between bone formation and resorption, resulting in a decline in both bone quantity and quality. Reactive oxygen species (ROS) activate nuclear factor kappa-B and mitogen-activated protein kinase signaling pathways, promoting osteoclastogenesis. Conversely, ROS hinder osteoblast differentiation by facilitating the binding of Forkhead box O proteins (FoxOs) to ß-catenin, triggering apoptosis through FoxOs-activating kinase phosphorylation. This results in increased osteoblastic receptor activator of nuclear factor kappa-B ligand (RANKL) expression and decreased nuclear factor erythroid 2-related factor 2 levels, compromising antioxidant defenses against oxidative damage. As CKD progresses, the accumulation of protein-bound uremic toxins such as indoxyl sulfate (IS) and p-cresyl sulfate (PCS) intensifies oxidative stress, primarily affecting osteoblasts. IS and PCS directly inhibit osteoblast viability, induce apoptosis, decrease alkaline phosphatase activity, and impair collagen 1 and osteonectin, impeding bone formation. They also reduce cyclic adenosine 3',5'-monophosphate (cAMP) production and lower parathyroid hormone (PTH) receptor expression in osteoblasts, resulting in PTH hyporesponsiveness. In summary, excessive production of ROS by uremic toxins not only reduces the number and function of osteoblasts but also induces PTH hyporesponsiveness, contributing to the initiation and progression of low bone turnover disease in CKD.

Sleep Duration and Kidney Function - Does Weekend Sleep Matter?

Objective: Weekend sleep duration is linked to health issues, including mortality. However, how weekend sleep duration can impact chronic kidney disease (CKD) still needs to be understood. Therefore, we aimed to analyze how weekend sleep duration is associated with kidney function. Methods: This is a cross-sectional study. Data were obtained from the 2017-2018 National Health and Nutrition Examination Survey. We included 5362 study participants and categorized them into nine subgroups by sleep duration (short: ≤6 hours, normal: 6-9 hours, and long: ≥9 hours) on weekdays and weekends and analyzed for the respective association with renal function using stratified multivariable linear regression. Results: Weekend sleep duration for 9 hours or more was associated with decreasing estimated glomerular filtration rate (eGFR) levels by 2.8 to 6.4 mL/min/1.73 m2 among people with long to short weekday sleep duration compared with short weekday and weekend sleep durations (control group) after adjusting for demographic characteristics, body measurement, sleep quality, smoking, and comorbidities. The study population with short weekday sleep duration (sWK) and long weekend sleep duration (lWD) had the most significant decline in eGFR. For the study population with sWK, eGFR level significantly decreased by 1.1 mL/min/1.73 m2 as sleep duration on weekends increased by one hour. Conclusion: The underlying mediators of lWD and CKD could be the dysregulation of human behaviors, metabolism, or biological functions. Longer weekend sleep duration was linked to a decrease in eGFR levels. It warrants further study to clarify the mediators.

Currently Used Methods to Evaluate the Efficacy of Therapeutic Drugs and Kidney Safety.

Kidney diseases with kidney failure or damage, such as chronic kidney disease (CKD) and acute kidney injury (AKI), are common clinical problems worldwide and have rapidly increased in prevalence, affecting millions of people in recent decades. A series of novel diagnostic or predictive biomarkers have been discovered over the past decade, enhancing the investigation of renal dysfunction in preclinical studies and clinical risk assessment for humans. Since multiple causes lead to renal failure, animal studies have been extensively used to identify specific disease biomarkers for understanding the potential targets and nephropathy events in therapeutic insights into disease progression. Mice are the most commonly used model to investigate the mechanism of human nephropathy, and the current alternative methods, including in vitro and in silico models, can offer quicker, cheaper, and more effective methods to avoid or reduce the unethical procedures of animal usage. This review provides modern approaches, including animal and nonanimal assays, that can be applied to study chronic nonclinical safety. These specific situations could be utilized in nonclinical or clinical drug development to provide information on kidney disease.

Influenza vaccination is associated with lower risk of renal cell carcinoma among chronic kidney disease patients: a population-based cohort study.

Background: Chronic kidney disease (CKD) patients possess a higher risk for renal cell carcinoma (RCC) possibly because of related underlying inflammation and immune dysregulation. In the current population-based cohort study, we evaluate the effects of influenza vaccination on RCC among CKD patients. Methods: We analysed the vaccinated and unvaccinated CKD patients (≥55 years of age) identified from the Taiwan National Health Insurance Database. Propensity score matching was used to reduce the selection bias. Subgroup analyses based on comorbid conditions, dialysis status and vaccinated dosages were also conducted. Results: The incidence of RCC decreased significantly in the vaccinated compared with unvaccinated group {unadjusted hazard ratio [HR] 0.50 [95% confidence interval (CI) 0.31-0.81], P < .01; adjusted HR 0.46 [95% CI 0.28-0.75], P < .01}. Such protective effects of influenza vaccination were noted significantly among those ≥75 years of age [unadjusted HR 0.29 (95% CI 0.12-0.74), P < .01; adjusted HR 0.22 (95% CI 0.08-0.58), P < .01]. A reverse association was noted between the total number of vaccinations and RCC events in both unadjusted and adjusted models. The Kaplan-Meier estimates of the RCC events showed significantly higher free survival rates in the vaccinated as compared with the unvaccinated patients (logrank P = .005). Conclusion: This population-based cohort study found a significant inverse relationship between influenza vaccination and the risk of RCC in CKD patients and the protective effects were more prominent in patients >75 years of age. A possible relation exists between the total number of vaccinations and RCC events. Future randomized clinical and basic studies will be needed to prove these findings and underlying pathophysiological mechanisms.

Effect of Annual Influenza Vaccination on the Risk of Lung Cancer Among Patients With Hypertension: A Population-Based Cohort Study in Taiwan.

Objectives: Lung cancer is a main contributor to all newly diagnosed cancers worldwide. The chemoprotective effect of the influenza vaccine among patients with hypertension remains unclear. Methods: A total of 37,022 patients with hypertension were retrospectively enrolled from the Taiwan National Health Insurance Research Database. These patients were further divided into a vaccinated group (n = 15,697) and an unvaccinated group (n = 21,325). Results: After adjusting for sex, age, comorbidities, medications, level of urbanization and monthly income, vaccinated patients had a significantly lower risk of lung cancer occurrence than unvaccinated patients (adjusted hazard ratio [aHR]: 0.56, 95% confidence interval [CI]: 0.47-0.67). A potential protective effect was observed for both sexes and in the elderly age group. With a greater total number of vaccinations, a potentially greater protective effect was observed (aHR: 0.75, 95% CI 0.60-0.95; aHR: 0.66, 95% CI: 0.53-0.82; aHR: 0.26, 95% CI: 0.19-0.36, after receiving 1, 2-3 and ≥4 vaccinations, respectively). Conclusion: Influenza vaccination was associated with a lower risk of lung cancer among patients with hypertension. The potentially chemoprotective effect appeared to be dose dependent.

Indoxyl sulfate induced frailty in patients with end-stage renal disease by disrupting the PGC-1α-FNDC5 axis.

OBJECTIVE: Sarcopenia or frailty is common among patients with chronic kidney disease (CKD). The protein-bound uremic toxin indoxyl sulfate (IS) is associated with frailty. IS induces apoptosis and disruption of mitochondrial activity in skeletal muscle. However, the association of IS with anabolic myokines such as irisin in patients with CKD or end-stage renal disease (ESRD) is unclear. This study aims to elucidate whether IS induces frailty by dysregulating irisin in patients with CKD. MATERIALS AND METHODS: The handgrip strength of 53 patients, including 28 patients with ESRD, was examined. Serum concentrations of IS and irisin were analyzed. CKD was established in BALB/c mice through 5/6 nephrectomy. Pathologic analysis of skeletal muscle was assessed through haematoxylin and eosin and Masson's trichrome staining. Expression of peroxisome proliferator-activated receptor-gamma coactivator PGC-1α and irisin were analyzed using real-time polymerase chain reaction and Western blotting. RESULTS: Handgrip strength was lower among patients with ESRD than among those without ESRD. In total, 64.3% and 24% of the patients in the ESRD and control groups had low handgrip strength, respectively (p < 0.05). Serum concentrations of IS were significantly higher in the ESRD group than in the control group (222.81 ± 90.67 µM and 23.19 ± 33.28 µM, respectively, p < 0.05). Concentrations of irisin were lower in the ESRD group than in the control group (64.62 ± 32.64 pg/mL vs. 99.77 ± 93.29 pg/mL, respectively, p < 0.05). ROC curves for low handgrip strength by irisin and IS were 0.298 (95% confidence interval (CI): 0.139-0.457, p < 0.05) and 0.733 (95% CI: 0.575-0.890, p < 0.05), respectively. The percentage of collagen was significantly higher in mice with 5/6 nephrectomy than in the control group. After resveratrol (RSV) treatment, the percentage of collagen significantly decreased. RSV modulates TGF-ß signaling. In vitro analysis revealed that IS treatment suppressed expression of PGC-1α and FNDC5 in a dose-dependent manner, whereas RSV treatment attenuated IS-induced phenomena in C2C12 cells. CONCLUSION: IS was positively correlated with frailty in patients with ESRD through the modulation of the PGC-1α-FNDC5 axis. RSV may be a potential drug for reversing IS-induced suppression of the PGC-1α-FNDC5 axis in skeletal muscle.

Transitions of dialysis status and outcomes after the unplanned first dialysis: a nationwide population-based cohort study.

In Taiwan, most first-time dialysis was started without the creation of an arteriovenous shunt. Here, we aimed to elucidate the transitions of dialysis status in the unplanned first dialysis patients and determine factors associated with their outcomes. A total of 50,315 unplanned first dialysis patients aged more than 18 years were identified from the National Health Insurance Dataset in Taiwan between 2001 and 2012. All patients were followed for 5 years for the transitions in dialysis status, including robust (dialysis-free), sporadic dialysis, continued dialysis, and death. Furthermore, factors associated with the development of continued dialysis and death were examined by the Cox proportional hazard models. After 5 years after the first dialysis occurrence, there were 5.39% with robust status, 1.67% with sporadic dialysis, 8.45% with continued dialysis, and 84.48% with death. Notably, we have identified common risk factors for developing maintenance dialysis and deaths, including male gender, older age, diabetes, coronary heart disease, stroke, heart failure, sepsis, and surgery. There was an extremely high mortality rate among the first unplanned dialysis patients in Taiwan. Less than 10% of these patients underwent continued dialysis during the 5-year follow-up period. This study highlighted the urgent need for interventions to improve patient outcomes.

Drug repurposing screens to identify potential drugs for chronic kidney disease by targeting prostaglandin E2 receptor.

Renal inflammation and fibrosis are significantly correlated with the deterioration of kidney function and result in chronic kidney disease (CKD). However, current therapies only delay disease progression and have limited treatment effects. Hence, the development of innovative therapeutic approaches to mitigate the progression of CKD has become an attractive issue. To date, the incidence of CKD is still increasing, and the biomarkers of the pathophysiologic processes of CKD are not clear. Therefore, the identification of novel therapeutic targets associated with the progression of CKD is an attractive issue. It is a critical necessity to discover new therapeutics as nephroprotective strategies to stop CKD progression. In this research, we focus on targeting a prostaglandin E2 receptor (EP2) as a nephroprotective strategy for the development of additional anti-inflammatory or antifibrotic strategies for CKD. The in silico study identified that ritodrine, dofetilide, dobutamine, and citalopram are highly related to EP2 from the results of chemical database virtual screening. Furthermore, we found that the above four candidate drugs increased the activation of autophagy in human kidney cells, which also reduced the expression level of fibrosis and NLRP3 inflammasome activation. It is hoped that these findings of the four candidates with anti-NLRP3 inflammasome activation and antifibrotic effects will lead to the development of novel therapies for patients with CKD in the future.

Indoxyl sulfate mediates low handgrip strength and is predictive of high hospitalization rates in patients with end-stage renal disease.

Background and aims: Sarcopenia has a higher occurrence rate in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD) than in the general population. Low handgrip strength-and not sarcopenia per se-is associated with clinical outcomes in patients with CKD, including cardiovascular mortality and hospitalization. The factors contributing to low handgrip strength are still unknown. Accordingly, this study aimed to determine whether uremic toxins influence low handgrip strength in patients with CKD. Materials and methods: This cohort study lasted from August 2018 to January 2020. The participants were divided into three groups: the control group [estimated glomerular filtration rate (eGFR) ≥ 60 ml/min], an advanced CKD group (eGFR = 15-60 ml/min), and an ESRD group (under maintenance renal replacement therapy). All participants underwent handgrip strength measurement, dual-energy X-ray absorptiometry, and blood sampling for myokines (irisin, myostatin, and interleukin 6) and indoxyl sulfate. Sarcopenia was defined according to the Asian Working Group for Sarcopenia consensus as low appendicular skeletal muscle index (appendicular skeletal muscle/height2 of < 7.0 kg/m2 in men and < 5.4 kg/m2 in women) and low handgrip strength (< 28 kg in men and < 18 kg in women). Results: Among the study participants (control: n = 16; CKD: n = 17; and ESRD: n = 42), the ESRD group had the highest prevalence of low handgrip strength (41.6 vs. 25% and 5.85% in the control and CKD groups, respectively; p < 0.05). The sarcopenia rate was similar among the groups (12.5, 17.6, and 19.5% for the control, CKD, and ESRD groups, respectively; p = 0.864). Low handgrip strength was associated with high hospitalization rates within the total study population during the 600-day follow-up period (p = 0.02). The predictions for cardiovascular mortality and hospitalization were similar among patients with and without sarcopenia (p = 0.190 and p = 0.094). The serum concentrations of indoxyl sulfate were higher in the ESRD group (227.29 ± 92.65 µM vs. 41.97 ± 43.96 µM and 6.54 ± 3.45 µM for the CKD and control groups, respectively; p < 0.05). Myokine concentrations were similar among groups. Indoxyl sulfate was associated with low handgrip strength in univariate and multivariate logistic regression models [univariate odds ratio (OR): 3.485, 95% confidence interval (CI): 1.372-8.852, p = 0.001; multivariate OR: 8.525, 95% CI: 1.807-40.207, p = 0.007]. Conclusion: Handgrip strength was lower in the patients with ESRD, and low handgrip strength was predictive of hospitalization in the total study population. Indoxyl sulfate contributed to low handgrip strength and counteracted the benefits of myokines in patients with CKD.

Risk of dialysis and renal diseases in patients with anorexia nervosa in Taiwan.

OBJECTIVE: To investigate the incidence and risk of renal-related complications in a nationwide cohort of Taiwanese patients with anorexia nervosa (AN). METHOD: This longitudinal cohort study analyzed the data of 43,951 individuals-comprising 2091 patients with AN and their controls matched (1:20) using propensity scores according to sex, age, degree of urbanization of residence, socioeconomic status, and year of diagnosis-from a population-based health insurance database; the study lasted 16 years. We used Kaplan-Meier curves to estimate the cumulative incidence of renal events. We also performed Cox proportional regression and constructed a risk model with death as a competing event (both adjusted for basic characteristics, renal diseases, and psychiatric comorbidities) to examine the risk of dialysis and renal outcomes in the AN group relative to the control group. RESULTS: In total, 204 and 10 patients with AN had renal-related outcomes and end-stage renal disease (ESRD), respectively. The cumulative incidence rates of all renal outcomes and ESRD in the AN group were 10.72% and .64%, respectively, at 10-year follow-up. Compared with the control group, the AN group had a significantly higher risk of acute dialysis (adjusted hazard ratio 2.10 [95% confidence interval 1.19-3.68]), hypokalemia, hypovolemia, nephritis, acute renal failure, and chronic renal failure. The AN group did not have a significantly higher risk of ESRD. DISCUSSION: The elevated risks of acute dialysis and some renal outcomes in AN highlight the importance of monitoring electrolyte imbalance and renal malfunctioning. PUBLIC SIGNIFICANCE: Malnutrition and purging behaviors may cause renal complications in patients with AN. In this longitudinal cohort study, we found that the 10-year cumulative incidence of all renal outcomes in AN was 10.72%, and that patients with AN had a two-fold higher risk of overall renal outcomes compared with those without AN. Our findings imply that weight restoration and ceasing purging behaviors are crucial for recovery from AN.

Factors Influencing Self-Management Behaviors among Hemodialysis Patients.

AIM: To investigate the factors affecting hemodialysis patients' self-management ability at a dialysis center in Taiwan. BACKGROUND: Taiwan has the highest incidence and prevalence of end-stage kidney disease (ESKD) in the world. Over 90% of patients with ESKD receiving hemodialysis (HD) and self-management behaviors are critical among these patients. Failure to adhere to self-managed care increases the cost of medical care and the risk of morbidity and mortality. METHODS: In this cross-sectional study, a total of 150 HD patients were observed for their self-management behaviors and the factors influencing these behaviors including education level, comorbid conditions, biochemical analysis, depression, and social support, etc., were analyzed. RESULTS: Self-management behaviors in HD patients were significantly impaired in the presence of diabetes mellitus, hypertension, anemia, hypoalbuminemia, and depression. The major predictor of patients' self-management was depression, explaining 14.8% of the total variance. Further addition of social support, hypertension, and diabetes mellitus into the regression model increased the total explained variance to 28.6%. Of the various domains of self-management, the partnership domain received the highest score, whereas emotional processing received the lowest score. CONCLUSIONS: This study found the important factors influencing self-management behaviors; through this acknowledgement and early correction of these factors, we hope to improve HD patients' individual life quality and further decrease their morbidity and mortality.

Effect of Dialysis Modalities on All-Cause Mortality and Cardiovascular Mortality in End-Stage Kidney Disease: A Taiwan Renal Registry Data System (TWRDS) 2005-2012 Study.

Introduction: End-stage kidney disease (ESKD) patients who need renal replacement therapy need to face a dialysis modality decision: the choice between hemodialysis (HD) and peritoneal dialysis (PD). Although the global differences in HD/PD penetration are affected by health-care policies, these two modalities may exert different effects on survival in patients with ESKD. Although Taiwan did not implicate PD as first policy, we still need to compare patients' outcomes using two modalities in a nation-wise database to determine future patients' care and health policies. Methods: We used the nationwide Taiwan Renal Registry Data System (TWRDS) database from 2005 to 2012 and included 52,900 patients (48,371 on HD and 4529 on PD) to determine all-cause and cardiovascular mortality among ESKD patients. Results: Age-matched survival probability from all-cause mortality was significantly lower in patients on PD than in those on HD (p < 0.05). The adjusted hazard ratios of 3-year and 5-year all-cause and cardiovascular mortality were significantly higher in PD compared with HD. The presence of comorbid conditions including myocardial infarction, coronary artery disease (CAD), diabetes mellitus (DM), hypoalbuminemia, hyperferritinemia and hypophosphatemia was related with significantly higher all-cause and CV mortality in PD patients. No significant difference was noted among younger patients <45 years of age regardless of DM and/or comorbid conditions. Conclusion: Although PD did not have the survival advantage compared to HD in all dialysis populations, PD was related with superior survival in younger non-DM patients, regardless of the presence of comorbidities. Similarly, for younger ESKD patients without the risk of CV disease, both PD and HD would be suitable dialysis modalities.

Role of Calcimimetics in Treating Bone and Mineral Disorders Related to Chronic Kidney Disease.

Renal osteodystrophy is common in patients with chronic kidney disease and end-stage renal disease and leads to the risks of fracture and extraosseous vascular calcification. Secondary hyperparathyroidism (SHPT) is characterized by a compensatory increase in parathyroid hormone (PTH) secretion in response to decreased renal phosphate excretion, resulting in potentiating bone resorption and decreased bone quantity and quality. Calcium-sensing receptors (CaSRs) are group C G-proteins and negatively regulate the parathyroid glands through (1) increasing CaSR insertion within the plasma membrane, (2) increasing 1,25-dihydroxy vitamin D3 within the kidney and parathyroid glands, (3) inhibiting fibroblast growth factor 23 (FGF23) in osteocytes, and (4) attenuating intestinal calcium absorption through Transient Receptor Potential Vanilloid subfamily member 6 (TRPV6). Calcimimetics (CaMs) decrease PTH concentrations without elevating the serum calcium levels or extraosseous calcification through direct interaction with cell membrane CaSRs. CaMs reduce osteoclast activity by reducing stress-induced oxidative autophagy and improving Wnt-10b release, which promotes the growth of osteoblasts and subsequent mineralization. CaMs also directly promote osteoblast proliferation and survival. Consequently, bone quality may improve due to decreased bone resorption and improved bone formation. CaMs modulate cardiovascular fibrosis, calcification, and renal fibrosis through different mechanisms. Therefore, CaMs assist in treating SHPT. This narrative review focuses on the role of CaMs in renal osteodystrophy, including their mechanisms and clinical efficacy.

Matrix metalloproteinase-7 promotes chronic kidney disease progression via the induction of inflammasomes and the suppression of autophagy.

Deposition of extracellular matrix (ECM), epithelial-mesenchymal transition (EMT) and inflammation are crucial processes in chronic kidney disease (CKD) progression. The matrix metalloproteinases (MMPs) belong to a major enzyme group of proteinases that are involved in ECM degradation. MMP controls multiple biological processes, such as cell proliferation, EMT and apoptosis. The present study identified the roles of MMP7 in CKD progression. We demonstrated the transcriptional profiles of MMPs in kidney tissues of CKD patients in the Gene Expression Omnibus (GEO) data repository. MMP7 mRNA level was markedly upregulated in kidney tissues of CKD patients. MMP7 overexpression activated the NLRP3 and NLRP6 inflammasomes and increased fibrosis-related proteins in kidney cells. MMP7 inhibited oxidative stress-induced apoptosis and rapamycin-induced autophagy. We found that MMP7 expression in the kidney was increased in various CKD animal models. Knockdown of MMP7 affected renal function and renal fibrosis in a folic acid-induced CKD model. The inhibition of MMP7 decreased fibrosis and NLRP3 and NLRP6 inflammasomes and induced autophagy in kidney tissues. Taken together, these results provide insight into targeting MMP7 as a therapeutic strategy for CKD.

Investigation of potential descriptors of chemical compounds on prevention of nephrotoxicity via QSAR approach.

Drug-induced nephrotoxicity remains a common problem after exposure to medications and diagnostic agents, which may be heightened in the kidney microenvironment and deteriorate kidney function. In this study, the toxic effects of fourteen marked drugs with the individual chemical structure were evaluated in kidney cells. The quantitative structure-activity relationship (QSAR) approach was employed to investigate the potential structural descriptors of each drug-related to their toxic effects. The most reasonable equation of the QSAR model displayed that the estimated regression coefficients such as the number of ring assemblies, three-membered rings, and six-membered rings were strongly related to toxic effects on renal cells. Meanwhile, the chemical properties of the tested compounds including carbon atoms, bridge bonds, H-bond donors, negative atoms, and rotatable bonds were favored properties and promote the toxic effects on renal cells. Particularly, more numbers of rotatable bonds were positively correlated with strong toxic effects that displayed on the most toxic compound. The useful information discovered from our regression QSAR models may help to identify potential hazardous moiety to avoid nephrotoxicity in renal preventive medicine.

Severe acute kidney disease is associated with worse kidney outcome among acute kidney injury patients.

Acute kidney disease (AKD) comprises acute kidney injury (AKI). However, whether the AKD staging system has prognostic values among AKI patients with different baseline estimated glomerular filtration (eGFR) remains a controversial issue. Algorithm-based approach was applied to identify AKI occurrence and to define different AKD stages. Risk ratio for major adverse kidney events (MAKE), including (1) eGFR decline > 35% from baseline, (2) initiation of dialysis, (3) in-hospital mortality of different AKD subgroups were identified by multivariable logistic regression. Among the 4741 AKI patients identified from January 2015 to December 2018, AKD stages 1-3 after AKI was common (53% in the lower baseline eGFR group and 51% in the higher baseline eGFR group). In the logistic regression model adjusted for demographics and comorbidities at 1-year follow-up, AKD stages 1/2/3 (AKD stage 0 as reference group) were associated with higher risks of MAKE (AKD stage: odds ratio, 95% confidence interval [95% CI], AKD 1: 1.85, 1.56-2.19; AKD 2: 3.43, 2.85-4.12; AKD 3: 10.41, 8.68-12.49). Regardless of baseline eGFR, staging criteria for AKD identified AKI patients who were at higher risk of kidney function decline, dialysis and mortality. Post-AKI AKD patients with severer stage need intensified care and timely intervention.