Pathophysiology Of Chronic Kidney Disease Research Articles

#417 Targeting parietal epithelial cell activation with mineralocorticoid receptor antagonism controls FSGS and crescentic glomerulonephritis

Abstract Background and Aims We have recently demonstrated that targeting specific pathways in parietal epithelial cells (PEC) can markedly alleviate experimental extracapillary glomerular injury [1]. Accumulating evidence has indicated the potential contributions of the mineralocorticoid receptor (MR) to the pathophysiology of chronic kidney disease. MR is expressed in endothelial cells, glomerular mesangial cells, podocytes, and distal tubular cells. Previous studies have shown that administering mineralocorticoid receptor antagonists has beneficial effects in various renal injury animal models, the role of the MR in extracapillary glomerulopathies is still elusive and mechanistically unclear. Methods To investigate the cell-specific role of the MR in PEC in the course of focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (GN), we generated chimeric mice specifically lacking MR (Pec Cre Nr3c2lox/lox) in PECs using an inducible Cre recombinase system. Maladaptive FSGS was induced by combining a high-salt diet and deoxycorticosterone acetate (DOCA) with unilateral nephrectomy (DOCA-UniN). Crescentic glomerulonephritis (GN) was induced using the anti-glomerular basement membrane nephrotoxic serum (NTS) model. Results At baseline, Pec Cre Nr3c2wt/wt and Pec Cre Nr3c2lox/lox mice displayed no kidney morphology and function differences. When challenged by DOCA-UniN, PEC-selective Nr3c2 targeting significantly inhibited the expression of PEC activation markers Ki67, CD44, and FSGS lesions. Importantly, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function compared to Pec Cre Nr3c2 wt/wt counterparts. Likewise, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function in the NTS-induced CGN model. Crescents were also more numerous and organised in Pec Cre Nr3c2wt/wt mice than in Pec Cre Nr3c2lox/lox animals. Next, we examined whether pharmacological MR inhibition could alleviate the severity of crescentic GN. When Pec Cre Nr3c2wt/wt mice were orally given eplerenone for 14 days after the onset of the crescentic GN, they were significantly protected from renal injury and failure (decreased proteinuria, normal BUN and reduced number of crescent). Such global action was associated with less expression of the CD44 activation marker on PECs. Thus, genetic disruption of MR in PEC and pharmacological inhibition using eplerenone reduced glomerular expression of CD44 and crescent formation. Furthermore, kidney biopsies of individuals diagnosed with crescentic glomerulonephritis displayed increased expression of MR in PEC within FSGS and crescents. We next evaluated PEC migration under various conditions (DMSO, HB-EGF, Eplerenone, or HB-EGF+Eplerenone) for 24 hours. Eplerenone fully abrogated HB-EGF-induced PEC migration and Pcna, Snai1, and Vim mRNA expressions. Conclusion Altogether, these results indicate the critical role of MR in PEC activation during crescentic glomerulonephritis, along with the recently discovered CD9/EGFR/PDGFR [1] and CLDN1 pathways. This further supports the idea that the PEC phenotype switch is not a bystander event but plays a targetable critical active pathogenic role in FGSS and, more surprisingly, in crescentic GN. MR modulation using eplerenone may be a new therapeutic option for the management of such severe disease.

Optimization and validation of metabolomics methods for feline urine and serum towards application in veterinary medicine

BackgroundMetabolomics is an emerging and powerful technology that offers a comprehensive view of an organism's physiological status. Although widely applied in human medicine, it is only recently making its introduction in veterinary medicine. As a result, validated metabolomics protocols in feline medicine are lacking at the moment. Since biological interpretation of metabolomics data can be misled by the extraction method used, species and matrix-specific optimized and validated metabolomic protocols are sorely needed. ResultsSystematic optimization was performed using fractional factorial experiments for both serum (n=57) and urine (n=24), evaluating dilution for both matrices, and aliquot and solvent volume, protein precipitation time and temperature for serum. For the targeted (n=76) and untargeted (n=1,949) validation of serum respectively, excellent instrumental, intra-assay and inter-day precision were observed (CV≤ 15% or 30%, respectively). Linearity deemed sufficient both targeted and untargeted (R2≥0.99 or 0.90, respectively). An appropriate targeted recovery between 70 and 130% was achieved. For the targeted (n=69) and untargeted (n=2,348) validation of the urinary protocol, excellent instrumental and intra-assay precision were obtained (CV≤ 15% or 30%, respectively). Subsequently, the discriminative ability of our metabolomics methods was confirmed for feline chronic kidney disease (CKD) by univariate statistics (n=41 significant metabolites for serum, and n=55 for urine, p-value<0.05) and validated OPLS-DA models (R2(Y)>0.95, Q2(Y)>0.65, p-value<0.001 for both matrices). SignificanceThis study is the first to present an optimized and validated wholistic metabolomics methods for feline serum and urine using ultra-high performance liquid chromatography coupled to quadrupole-Orbitrap high-resolution mass spectrometry. This robust methodology opens avenues for biomarker panel selection and a deeper understanding of feline CKD pathophysiology and other feline applications.

Chronic Kidney Disease Diets for Kidney Failure Prevention: Insights from the IL-11 Paradigm.

Nearly every fifth adult in the United States and many older adults worldwide are affected by chronic kidney disease (CKD), which can progress to kidney failure requiring invasive kidney replacement therapy. In this review, we briefly examine the pathophysiology of CKD and discuss emerging mechanisms involving the physiological resolution of kidney injury by transforming growth factor beta 1 (TGFβ1) and interleukin-11 (IL-11), as well as the pathological consequences of IL-11 overproduction, which misguides repair processes, ultimately culminating in CKD. Taking these mechanisms into account, we offer an overview of the efficacy of plant-dominant dietary patterns in preventing and managing CKD, while also addressing their limitations in terms of restoring kidney function or preventing kidney failure. In conclusion, this paper outlines novel regeneration strategies aimed at developing a reno-regenerative diet to inhibit IL-11 and promote repair mechanisms in kidneys affected by CKD.

Inequalities in emergency care use across transition from paediatric to adult care: a retrospective cohort study of young people with chronic kidney disease in England.

Sociodemographic inequalities in emergency secondary care usage were evident in this cohort across the transition period, independent of age, with some variation between admissions and A&E use, and evidence of effect modification by transfer. Such inequalities likely have multifactorial origin, but importantly, could represent differential meetings of care needs. • In chronic kidney disease (CKD), transfer from paediatric to adult healthcare is associated with declining health outcomes. • Known differences in CKD outcomes by sociodemographic factors have limited prior exploration in the context of transfer. • Population-level data was used to examine the impacts of transfer and sociodemographic factors on unplanned secondary care utilisation in CKD. • Healthcare utilisation trends may not reflect known CKD pathophysiology and there may be unexplored sociodemographic inequalities in the experiences of young people across transfer.

Mineralocorticoid receptor antagonists in kidney transplantation.

The fundamental role of the renin-angiotensin-aldosterone system in the pathophysiology of chronic kidney disease, congestive heart failure, hypertension and proteinuria is well established in pre-clinical and clinical studies. Mineralocorticoid receptor antagonists are among the primary options for renin-angiotensin-aldosterone system blockage, along with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers. In this narrative review, we aim to evaluate the efficiency and safety of mineralocorticoid receptor antagonists in kidney transplant recipients, including the potential underlying pathophysiology. The efficiency and safety of mineralocorticoid receptor antagonists in managing chronic kidney disease and proteinuria, either non-nephrotic or nephrotic range, have been demonstrated among nontransplanted patients, though studies investigating the role of mineralocorticoid receptor antagonists among kidney transplant recipients are scarce. Nevertheless, promising results have been reported in pre-clinical and clinical studies among kidney transplant recipients regarding the role of mineralocorticoid receptor antagonists in terms of ischaemia-reperfusion injury, proteinuria, or calcineurin inhibitor-mediated nephrotoxicity without considerable adverse events such as hypotension, hyperkalaemia or worsening renal functions. Even though initial results regarding the role of mineralocorticoid receptor antagonist therapy for kidney transplant recipients are promising, there is clear need for large-scale randomized clinical trials with long-term follow-up data.

Integration of Urinary Peptidome and Fecal Microbiome to Explore Patient Clustering in Chronic Kidney Disease.

Millions of people worldwide currently suffer from chronic kidney disease (CKD), requiring kidney replacement therapy at the end stage. Endeavors to better understand CKD pathophysiology from an omics perspective have revealed major molecular players in several sample sources. Focusing on non-invasive sources, gut microbial communities appear to be disturbed in CKD, while numerous human urinary peptides are also dysregulated. Nevertheless, studies often focus on isolated omics techniques, thus potentially missing the complementary pathophysiological information that multidisciplinary approaches could provide. To this end, human urinary peptidome was analyzed and integrated with clinical and fecal microbiome (16S sequencing) data collected from 110 Non-CKD or CKD individuals (Early, Moderate, or Advanced CKD stage) that were not undergoing dialysis. Participants were visualized in a three-dimensional space using different combinations of clinical and molecular data. The most impactful clinical variables to discriminate patient groups in the reduced dataspace were, among others, serum urea, haemoglobin, total blood protein, urinary albumin, urinary erythrocytes, blood pressure, cholesterol measures, body mass index, Bristol stool score, and smoking; relevant variables were also microbial taxa, including Roseburia, Butyricicoccus, Flavonifractor, Burkholderiales, Holdemania, Synergistaceae, Enterorhabdus, and Senegalimassilia; urinary peptidome fragments were predominantly derived from proteins of collagen origin; among the non-collagen parental proteins were FXYD2, MGP, FGA, APOA1, and CD99. The urinary peptidome appeared to capture substantial variation in the CKD context. Integrating clinical and molecular data contributed to an improved cohort separation compared to clinical data alone, indicating, once again, the added value of this combined information in clinical practice.

Endothelin receptor antagonists in diabetic and non-diabetic chronic kidney disease.

Chronic kidney disease (CKD) is one of the major causes of morbidity and mortality, affecting >800 million persons globally. While we still lack efficient, targeted therapies addressing the major underlying pathophysiologic processes in CKD, findings of several recent trials have brought about a shifting landscape of promising therapies. The endothelin system has been implicated in the pathophysiology of CKD and endothelin receptor antagonists are one class of drugs for which we have increasing evidence of efficacy in these patients. In this review we summarize the most recent findings on the safety and efficacy of endothelin receptor antagonists in diabetic and non-diabetic CKD, future directions of research and upcoming treatments.

Renal rehabilitation learning in Japanese physical therapy schools: a fact-finding study

BackgroundThe scope and content of pregraduate education in renal rehabilitation, a comprehensive program for patients with chronic kidney disease (CKD), at training institutions remain unclear. Therefore, this cross-sectional study aimed to evaluate the state of renal rehabilitation education at physical therapy schools in Japan via a survey.MethodsQuestionnaire forms were distributed to instructors responsible for physical therapy across 277 physical therapy schools in Japan. The questionnaire comprised items that assessed the opinions of the respondents on the necessity of learning renal rehabilitation during their student days and after graduation and the content covered at institutions that offered classes on renal rehabilitation. The participating institutions were divided into Renal Rehab Education and No Renal Rehab Education groups. Fisher’s exact and chi-squared tests were used to compare variables between the groups.ResultsAmong the 154 schools that responded to the survey between 14 June 2023 and 31 August 2023 (response rate 55.6%), 123 schools (79.9%) were included in the Renal Rehab Education group. The percentage of classes on rehabilitation for patients with endocrine/metabolic diseases, digestive system diseases, and cancer was higher in the Renal Rehab Education group than that in the No Renal Rehab Education group (P = 0.02, P < 0.001, and P = 0.003, respectively). The distribution of the perceived need to learn renal rehabilitation during student days and after graduation differed significantly between the Renal Rehab Education and No Renal Rehab Education groups (P < 0.001 and P = 0.004, respectively). Exercise therapy for patients with CKD (83.7%); definition, diagnosis, severity classification, and testing for CKD (81.3%); general remarks on renal rehabilitation (80.5%); pathophysiology of CKD (78.9%); and renal replacement therapy (69.9%) were the most frequently implemented contents. Prioritization of other fields (45.2%), insufficient class hours (41.9%), and lack of specialized faculty (38.7%) were identified as reasons for not implementing renal rehabilitation courses in the No Renal Rehab Education group; however, 77.4% of schools in this group aimed to commence courses in the future.ConclusionsApproximately 80% of physiotherapy schools offered renal rehabilitation courses. Awareness campaigns must be conducted to facilitate the widespread implementation of renal rehabilitation.

New marker for chronic kidney disease progression and mortality in medical-word virtual space

A new marker reflecting the pathophysiology of chronic kidney disease (CKD) has been desired for its therapy. In this study, we developed a virtual space where data in medical words and those of actual CKD patients were unified by natural language processing and category theory. A virtual space of medical words was constructed from the CKD-related literature (n = 165,271) using Word2Vec, in which 106,612 words composed a network. The network satisfied vector calculations, and retained the meanings of medical words. The data of CKD patients of a cohort study for 3 years (n = 26,433) were transformed into the network as medical-word vectors. We let the relationship between vectors of patient data and the outcome (dialysis or death) be a marker (inner product). Then, the inner product accurately predicted the outcomes: C-statistics of 0.911 (95% CI 0.897, 0.924). Cox proportional hazards models showed that the risk of the outcomes in the high-inner-product group was 21.92 (95% CI 14.77, 32.51) times higher than that in the low-inner-product group. This study showed that CKD patients can be treated as a network of medical words that reflect the pathophysiological condition of CKD and the risks of CKD progression and mortality.

Application of Electrolyzed Hydrogen Water for Management of Chronic Kidney Disease and Dialysis Treatment-Perspective View.

Chronic kidney disease (CKD), which is globally on the rise, has become an urgent challenge from the perspective of public health, given its risk factors such as end-stage renal failure, cardiovascular diseases, and infections. The pathophysiology of CKD, including dialysis patients, is deeply associated with enhanced oxidative stress in both the kidneys and the entire body. Therefore, the introduction of a safe and widely applicable antioxidant therapy is expected as a measure against CKD. Electrolyzed hydrogen water (EHW) generated through the electrolysis of water has been confirmed to possess chemical antioxidant capabilities. In Japan, devices producing this water have become popular for household drinking water. In CKD model experiments conducted to date, drinking EHW has been shown to suppress the progression of kidney damage related to hypertension. Furthermore, clinical studies have reported that systemic oxidative stress in patients undergoing dialysis treatment using EHW is suppressed, leading to a reduction in the incidence of cardiovascular complications. In the future, considering EHW as one of the comprehensive measures against CKD holds significant importance. The medical utility of EHW is believed to be substantial, and further investigation is warranted.

Exercise for patients with chronic kidney disease: from cells to systems to function.

Chronic kidney disease (CKD) is among the leading causes of death and disability, affecting an estimated 800 million adults globally. The underlying pathophysiology of CKD is complex creating challenges to its management. Primary risk factors for the development and progression of CKD include diabetes mellitus, hypertension, age, obesity, diet, inflammation, and physical inactivity. The high prevalence of diabetes and hypertension in patients with CKD increases the risk for secondary consequences such as cardiovascular disease and peripheral neuropathy. Moreover, the increased prevalence of obesity and chronic levels of systemic inflammation in CKD have downstream effects on critical cellular functions regulating homeostasis. The combination of these factors results in the deterioration of health and functional capacity in those living with CKD. Exercise offers protective benefits for the maintenance of health and function with age, even in the presence of CKD. Despite accumulating data supporting the implementation of exercise for the promotion of health and function in patients with CKD, a thorough description of the responses and adaptations to exercise at the cellular, system, and whole body levels is currently lacking. Therefore, the purpose of this review is to provide an up-to-date comprehensive review of the effects of exercise training on vascular endothelial progenitor cells at the cellular level; cardiovascular, musculoskeletal, and neural factors at the system level; and physical function, frailty, and fatigability at the whole body level in patients with CKD.

The role of glucocorticoid metabolism in the skeletal pathophysiology of chronic kidney disease

The role of glucocorticoid metabolism in the skeletal pathophysiology of chronic kidney disease

Postoperative Outcomes Among Dialysis Patients Undergoing Hip Fracture Repair.

Geriatric hip fractures are strongly correlated with increased morbidity. Even so, postoperative outcomes following surgical repair of hip fractures for patients with end stage renal disease lack extensive investigation. Chronic kidney disease (CKD) poses unique risks for surgical procedures as it has been associated with several complications. Little information is available regarding the outcomes of patients whose renal function decline necessitates dialysis usage. The purpose of this study was to compare post-surgical outcomes based on dialysis usage among CKD patients requiring hip fracture repair. We used the PearlDiver database to identify hip fracture repair patients diagnosed with stages 3, 4, and 5 CKD. We matched the populations according to patient characteristics and comorbidities. We then compared patient complication rates among dialyzed and non-dialyzed CKD patients following hip fracture repair at 30days, 90days, and 1year following the procedure. Dialyzed patients were more likely to experience myocardial infarction within 30days (P = .02) and 90days (P = .002). Dialyzed patients suffered cardiac arrest at higher rates within the same time intervals (P = .02; P = .002). Furthermore, dialysis patients developed sepsis (P = .005) and pneumonia (P = .005) at higher rates within 30days of operation. Dialysis patients did not have increased risk of blood transfusion within 30days of the operation (P = .07). We found significant increases in myocardial infarction, cardiac arrest, pneumonia, and sepsis risk among dialyzed CKD patients. Blood transfusion risk failed to reach statistical significance. Our findings are consistent with previous research regarding CKD pathophysiology and associated perioperative outcomes. Given the drastic decline of renal function among patients on dialysis, our findings may be attributable to decreased glomerular filtration rate in CKD as well as dialysis itself. Regardless, multidisciplinary collaboration should be employed when performing hip fracture repair on a patient who is actively undergoing hemodialysis.

High circulating endocan in chronic kidney disease? A systematic review and meta-analysis.

Chronic kidney disease (CKD) is one of the leading causes of morbidity and mortality worldwide. Endothelial dysfunction has been suggested to be involved in the pathophysiology of CKD. Endocan, as an endothelial factor, has been shown to increase in several diseases. The current systematic review and meta-analysis was performed with the aim of determining the association between endocan levels and CKD. Four international databases, including PubMed, Embase, Scopus, and Web of Science were searched for relevant studies. Afterward, screening and extraction of data were performed. We conducted a random-effect meta-analysis to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) to compare circulating endocan levels between patients with CKD (including patients undergoing hemodialysis) and healthy controls. Subgroup analysis based on the specimen in which endocan was measured (serum or plasma) was also performed. After screening by title/abstract and full-text review by the authors, 20 studies were included. Meta-analysis revealed that serum endocan is higher in CKD patients compared to healthy controls (SMD 1.34, 95% CI 0.20 to 2.48, p-value<0.01). This higher endocan level was also observed in the subgroup of studies that measured plasma endocan while this was not the case for the subgroup of studies assessing serum endocan. Meta-analysis was also performed for comparison of CKD patients without other comorbidities and healthy controls, which resulted in the same conclusion of higher endocan levels in patients with CKD (SMD 0.74, 95% CI 0.52 to 0.95, p-value<0.01). Moreover, endocan was associated with cardiovascular diseases in CKD. Our study demonstrated that endocan is significantly increased in patients with CKD. This can have clinical implications as well as highlight the need for future research investigating the diagnostic and prognostic role of endocan in CKD.

A functional MMP-9-1562C>T polymorphism, MMP-9 serum levels and nephrolithiasis risk in a southern Chinese population.

The role of matrix metalloproteinase 9 (MMP-9) in the pathophysiology of chronic kidney disease (CKD), which is associated with a nearly two-fold greater risk for urinary calculi compared to people without CKD, has been demonstrated. The aim of the research is to evaluate the association between MMP-9-1562C>T polymorphism, MMP-9 serum levels and nephrolithiasis risk. A hospital-based case-control study involving 302 kidney stone patients and 408 controls without kidney stone from southern China was conducted. Sanger sequencing was used to genotype the MMP-9-1562C>T polymorphism. The serum MMP-9 was measured in 105 kidney stone patients and 77 controls by enzyme-linked immunosorbent assay. Compared to the control group, the CT genotype was more frequent in nephrolithiasis patients (adjusted OR = 1.60, 95% CI = 1.09-2.37: the risk of developing nephrolithiasis in individuals with CT genotype compared to CC genotype). Moreover, there was also a higher frequency of CT/TT genotypes among patients with nephrolithiasis (adjusted OR = 1.49, 95% CI = 1.02-2.19: the risk of developing nephrolithiasis in individuals with CT/TT genotypes compared to CC genotype). The risk remained for the subgroups of patients aged >53, smokers with pack-years of smoking >20, non-drinkers, non-diabetic patients, patients with hypertension, recurrent episodes and calcium oxalate stones (OR = 2.26, 95% CI = 1.31-3.91; OR = 5.47, 95% CI = 1.10-27.30; OR = 1.76, 95% CI = 1.14-2.72; OR = 1.54, 95% CI = 1.03-2.30; OR = 1.97, 95% CI = 1.01-3.82; OR = 1.67, 95% CI = 1.06-2.62; OR = 1.54, 95% CI = 1.02-2.32, respectively). Biochemical parameters did not differ between genotypes. Compared to controls (18.57 ± 5.80 ng/mL), nephrolithiasis patients had significantly higher serum MMP-9 levels (30.17 ± 6.78 ng/mL, p < 0.001). The serum MMP-9 levels of patients with CT/TT genotypes of MMP-9-1562C>T were significantly higher than those with CC genotype (32.00 ± 6.33 vs. 29.13 ± 6.85 ng/mL, p = 0.037). The MMP-9-1562C>T polymorphism in association with its soluble protein increased the risk of kidney stone, thus suggesting it could be used as a susceptibility biomarker for nephrolithiasis. Further functional studies and larger studies that include environmental exposure data are needed to confirm the findings.

In vivo longitudinal 920 nm two-photon intravital kidney imaging of a dynamic 2,8-DHA crystal formation and tubular deterioration in the adenine-induced chronic kidney disease mouse model.

Chronic kidney disease (CKD) is one of the most common renal diseases manifested by gradual loss of kidney function with no symptoms in the early stage. The underlying mechanism in the pathogenesis of CKD with various causes such as high blood pressure, diabetes, high cholesterol, and kidney infection is not well understood. In vivo longitudinal repetitive cellular-level observation of the kidney of the CKD animal model can provide novel insights to diagnose and treat the CKD by visualizing the dynamically changing pathophysiology of CKD with its progression over time. In this study, using two-photon intravital microscopy with a single 920 nm fixed-wavelength fs-pulsed laser, we longitudinally and repetitively observed the kidney of an adenine diet-induced CKD mouse model for 30 days. Interestingly, we could successfully visualize the 2,8-dihydroxyadenine (2,8-DHA) crystal formation with a second-harmonics generation (SHG) signal and the morphological deterioration of renal tubules with autofluorescence using a single 920 nm two-photon excitation. The longitudinal in vivo two-photon imaging results of increasing 2,8-DHA crystals and decreasing tubular area ratio visualized by SHG and autofluorescence signal, respectively, were highly correlated with the CKD progression monitored by a blood test showing increased cystatin C and blood urea nitrogen (BUN) levels over time. This result suggests the potential of label-free second-harmonics generation crystal imaging as a novel optical technique for in vivo CKD progression monitoring.

Pathogenesis of Chronic Kidney Disease Is Closely Bound up with Alzheimer’s Disease, Especially via the Renin-Angiotensin System

Chronic kidney disease (CKD) is a clinical syndrome secondary to the definitive change in function and structure of the kidney, which is characterized by its irreversibility and slow and progressive evolution. Alzheimer's disease (AD) is characterized by the extracellular accumulation of misfolded β-amyloid (Aβ) proteins into senile plaques and the formation of neurofibrillary tangles (NFTs) containing hyperphosphorylated tau. In the aging population, CKD and AD are growing problems. CKD patients are prone to cognitive decline and AD. However, the connection between CKD and AD is still unclear. In this review, we take the lead in showing that the development of the pathophysiology of CKD may also cause or exacerbate AD, especially the renin-angiotensin system (RAS). In vivo studies had already shown that the increased expression of angiotensin-converting enzyme (ACE) produces a positive effect in aggravating AD, but ACE inhibitors (ACEIs) have protective effects against AD. Among the possible association of risk factors in CKD and AD, we mainly discuss the RAS in the systemic circulation and the brain.

Paraoxonase 1 and Chronic Kidney Disease: A Meta-Analysis.

Oxidative stress is known to be associated with the pathophysiology of chronic kidney disease (CKD). Paraoxonase 1 (PON1) is an antioxidant enzyme that has been proposed as a biomarker for CKD. While several studies have reported an association between serum PON1 activity and CKD, consensus based on systematically analyzed data remains necessary. We set out to conduct a meta-analysis of literature on PON1 in CKD. Electronic databases, such as MEDLINE, Embase and CENTRAL, were searched for available studies on PON1 activity in patients with CKD (without dialysis) as published before December 2022. A random-effects meta-analysis was performed. In total, 24 studies (22 studies on paraoxonase and 11 on arylesterase activity) were eligibly identified. Patients with CKD showed a lower activity of paraoxonase (standard mean difference [SMD], -1.72; 95% confidence interval [CI], -2.15 to -1.29) and arylesterase (SMD, -2.60; 95%CI, -3.96 to -1.24) than healthy controls. In the subgroup analyses, paraoxonase activity was lower in chronic kidney failure (CKF), an advanced stage of CKD, than in non-CKF. In summary, PON1 activity is low in patients with CKD, suggesting that the antioxidant defense by PON1 is impaired in CKD. The decrease in enzyme activity is pronounced in advanced CKD showing some variability depending on the substrate employed to measure PON1 activity. Further studies are warranted.

Chemerin levels in chronic kidney disease: A systematic review and meta-analysis.

Chemerin as an inflammatory biomarker has gained attention in its biomarker capability. Several studies measured its levels in chronic kidney disease (CKD), as one of the common non-communicable causes of mortality and morbidity. Hence, this systematic review and meta-analysis aimed to investigate this association. PubMed, Scopus, Embase, and the Web of Science databases were systematically searched for studies investigating chemerin levels in any CKD stage (including end-stage renal disease patients undergoing hemodialysis (HD)) and comparing it with healthy controls. Random effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI). A total of eight studies were included, comprised of 875 individuals, with a mean age of 56.92 ± 11.78 years. All studies had high quality based on the New Castle-Ottawa Scale (NOS). Meta-analysis revealed significantly higher levels of chemerin in CKD patients compared to healthy controls (SMD 2.15, 95% CI 0.83-3.48, p-value<0.01). Additionally, HD patients had statistically higher levels of chemerin than controls (SMD 2.10, 95% CI 0.58-3.62, p-value=0.01). In meta-regression, publication year accounted for 23.50% and 24.17% of heterogeneity for these analyses, respectively. Chemerin can be potentially used as a biomarker in CKD patients, which can suggest the inflammatory pathways for the disease. Further research is warranted for the assessment of its clinical applications and enlightening its role in the pathophysiology of CKD.

S-16-6: NATRIURETIC PEPTIDES AND HUMORAL FACTORS IN CARDIORENAL SYNDROME AND RESISTANT HYPERTENSION

Hypertension is one of the strongest and modifiable risk factors for cardiovascular disease, and a variety of antihypertensive agents and treatment modalities have been developed in these 6 decades. In Japan, however, among the patients with hypertension, ∼75% fail to reach an optimal goal of target blood pressure, and 10–15% of the patients are referred to as resistant hypertension. There are a number of factors for resistant hypertension; especially, the prevalence of resistant hypertension is reported to be 2–3 times higher in patients with chronic kidney disease (CKD) than in the general hypertensive population. CKD has become a major challenge to public health all over the world, and one of the reasons for increased morbidity should be the increasing prevalence of cardiometabolic (or metabolic kidney) disease including diabetic kidney disease. Considering them, novel therapeutic strategies are eagerly being sought. We have studied the roles of vasoactive hormones, such as natriuretic peptides and aldosterone, and local humoral regulators in the pathophysiology of CKD. We have especially focused on metabolic renal disease, including diabetic nephropathy, nephrosclerosis, and renal fibrosis as their common consequence. Using genetically engineered mouse models, we demonstrated the renoprotective role of natriuretic peptides (ANP, BNP) against diabetic nephropathy, immune-mediated renal injury as well as renal fibrosis by subtotal renal ablation. Furthermore, using natriuretic peptide receptor (GC-A)-deficient mice coupled with aldosterone-induced renal injury, we found a renoprotective role of natriuretic peptides on podocytes independent of their antihypertensive action, by inhibiting the local RAS-MAPK-cytokine cascade activation. From recent GWAS analyses, gene polymorphisms related to the natriuretic peptide system are found to be strongly associated with hypertension and cardiovascular disease, suggesting their critical role in cardiovascular homeostasis and blood pressure control. Angiotensin receptor-neprilysin inhibitor (ARNI) is a new class of anti-hypertensive agents characterized by its dual action with renin-angiotensin system blockade and inhibition of natriuretic peptide degradation. In recent clinical trials, ARNI has been shown to have significant cardio-renoprotective effects with a potent antihypertensive property. These findings together could show potential molecular targets, providing a promise for novel therapeutic approaches against CKD with resistant hypertension, metabolic renal disease and related cardiovascular complications.