Aging Kidney Research Articles

Aging and Chronic Kidney Disease: Epidemiology, Therapy, Management, and the Role of immunity

Abstract Chronic kidney disease (CKD) is now an unquestionable progressive condition that affects more than 10% of the general population worldwide, and has emerged as one of the most important causes of global mortality. It is clear that the prevalence of CKD among aging population is significantly elevated. It involves a board range of complex and poorly understood concerns in older adults such as frailty, malnutrition, sarcopenia, and even cognitive and mental dysfunction. In kidneys, renal function such as glomerular filtration, urine concentration and dilution, and homeostasis of sodium and potassium, can be influenced by the aging process. In addition, it's worth noting that CKD and end stage of kidney disease (ESRD) patients are often accompanied by an activation of immune system and inflammation. It involves both the innate and adaptive immune system. Based on these backgrounds, in this review article, we attempt to summarize the epidemiological characteristics of CKD in aging population, discuss the immunological mechanisms in aging-related CKD, and furnish the reader with the process in therapy and management for elderly patients with CKD.

Single-cell transcriptome sequencing partially revealed the changes of T cells in the early stage of aging kidney

Aging is a gradual, inevitable physiologic process. The organ aging is related to the persistence of chronic inflammation, but the understanding of inflammatory state during renal aging is lacking currently. Single-cell transcriptome sequencing was performed on aging mouse kidney to reveal the molecular phenotype and composition changes of different cell types. In the early stage of aging, immune cells such as T, B cells and mononuclear macrophages increased in kidney. The molecular state of T cells in aging kidney changed and polarized. Among them, we identified a group of GZMK+ CD8 + T cells with high expression of Eomes, Pdcd1 and Ifng and a group of Il17a+ T cells with high expression of Il17a and Il23r. Moreover, the cytokines and inflammations can aggravate tissue damage eventually. Furthermore, we found the interaction between different types of epithelial cells and T cells increased during the renal aging. These results identify the changes of T cells in the early stage of aging kidney and suggest that GZMK+CD8+ T cells might be a potential target to ameliorate age-associated dysfunctions of kidney(Graphical Abstract).

Contrast-induced nephropathy: nursing interventions - a scoping review

Abstract Introduction Contrast-induced nephropathy (CIN) refers to a reduction in renal function following contrast administration, excluding other causes. It is characterized by na increase in creatinine levels of 0.5mg/dl or greater, or a 25% increase over baseline creatinine, occurring 48 to 72 hours post-contrast administration and lasting for 2 to 5 days (Santos et al., 2011). Antunes et al. (2013) refers that the CIN is the 3rd cause of acute renal insufficiency (ARI) and that CIN may develop in up to 55% of patients who receive contrast exposure during coronary angiography and of these may result in 12,6% requiring dialysis among high-risk groups following percutaneous coronary intervention (PCI) (Wu et al., 2022). Objective This review aims to map the available evidence regarding nursing interventions to prevent contrast-induced nephropathy in patients undergoing PCI. Methods The review follows the methodology proposed by the Joanna Briggs Institute guided by the PCC (Population, Concept, Context) strategy. Were identified 44 articles by MEDLINE Complete (via PubMed), CINAHL Complete (via EBSCO) e SciELO, and analyzed/ selected through PRISMA Scr flowchart. Four articles were included. Results These articles revealed that the incidence of CIN varies based on risk factors such as age, hypertension, and pre-existing chronic kidney disease. As there is no specific treatment for contrast-induced nephropathy, prevention strategies are essential. Nursing professionals have a significant and privileged role in the pre-, intra-, and post-procedural phases, and thus, are best positioned to implement prevention strategies for CIN. In general, hospitals that implemented improvement interventions reduced CIN by 21% compared to the pre-intervention phase. Compared to patients with pre-existing CKD, the reduction was 28% (Lambert et al., 2017). Teams also report important successes in implementing improvements, such as changing behavior with greater awareness of CIN prevention strategies, implementing the hydration protocol, standardizing medical prescriptions and minimizing the volume of contrast administered. Conclusions Nursing plays a crucial and privileged role in preventing CIN. Key interventions involve conducting a thorough initial assessment to identify individuals at risk for CIN (considering factors such as age, comorbidities, nephrotoxic medication, and dehydration). Pioli et al. (2023) found that oral hydration can be effective in the process of preventing CIN, before and after elective percutaneous procedures. It concluded that the oral hydration protocol carried out by nurses proved to be as effective as the hospital intravenous hydration protocol in protecting the kidneys of individuals at risk of developing CIN associated with elective coronary interventions (Picture 1). By implementing these strategies, nursing professionals can effectively contribute to reducing the incidence of contrast-induced nephropathy in patients undergoing PCI.

Development and validation of risk prediction model for post-donation renal function in living kidney donors

This study aimed to create and validate a predictive model for renal function following live kidney donation, using pre-donation factors. Accurately predicting remaining renal function post live kidney donation is currently insufficient, necessitating an effective assessment tool. A multicenter retrospective study of 2318 live kidney donors from two independent centers (May 2007–December 2019) was conducted. The primary endpoint was the reduction in eGFR to below 60 mL/min/m2 6 months post-donation. The primary endpoint was achieved in 14.4% of the training cohort and 25.8% of the validation cohort. Sex, age, BMI, hypertension, preoperative eGFR, and remnant kidney proportion (RKP) measured by computerized tomography (CT) volumetry were found significant in the univariable analysis. These variables informed a scoring system based on multivariable analysis: sex (male: 1, female: 0), age at operation (< 30: 0, 30–39: 1, 40–59: 2, ≥ 60: 3), preoperative eGFR (≥ 100: 0, 90–99: 2, 80–89: 4, < 80: 5), and RKP (≥ 52%: 0, < 52%: 1). The total score ranged from 0 to 10. The model showed good discrimination for the primary endpoint in both cohorts. The prediction model provides a useful tool for estimating post-donation renal dysfunction risk, factoring in the side of the donated kidney. It offers potential enhancement to pre-donation evaluations.

Association between dietary magnesium intake and all-cause mortality among patients with diabetic retinopathy: a retrospective cohort study of the NHANES 1999-2018.

This study aimed to investigate the association between dietary magnesium intake and all-cause mortality among diabetic retinopathy (DR) patients. In this retrospective cohort study, data of 1,034 DR patients were extracted from the National Health and Nutrition Examination Survey (NHANES) (1999-2018). Dietary magnesium data were obtained from two 24-hour dietary recall interviews, and categorized into quartiles. Potential confounders were selected using weighted univariate Cox regression models. Weighted univariate and multivariate Cox regression models were used to explore the association between dietary magnesium intake and all-cause mortality in DR patients. The results were presented with hazard ratios (HRs) and 95% confidence intervals (CIs). Associations were further explored for subgroups related to age, gender, cardiovascular disease, and chronic kidney disease. Our study included 1,034 DR patients, of whom 438 (42.36%) died. The mean age of all patients was 63.26 (0.51) years old, with a median follow-up time of 75.00 months. Higher magnesium intake was associated with lower all-cause mortality risk (HR=0.58, 95%CI: 0.38-0.88) in DR patients. The association remained for those aged <65 years (HR=0.35, 95%CI: 0.15-0.81), male patients (HR=0.48, 95%CI: 0.27-0.84), patients without chronic kidney disease (HR=0.43, 95%CI: 0.23-0.82), and patients with a history of cardiovascular disease (HR=0.63, 95%CI: 0.39-1.02). DR patients with adequate magnesium intake exhibited a lower incidence of all-cause mortality. Further studies are needed to validate our findings and explore the optimal strategy for magnesium supplementation in DR patients.

Epidemiological analysis disease of chronic renal failure in patients CKD on HD

Chronic Kidney Disease (CKD) It is defined as a decrease in kidney function caused by various factors that cause disease. The purpose of the research was to analyze the epidemiology of chronic kidney failure in patients CKD on HD. This research was carried out at the Hemodialysis Installation of M.M. Dunda Limboto Hospital, Gorontalo Regency, Gorontalo Province, Indonesia. The type of research is observational research using a cross sectional design. The data used in this research are primary data and secondary data. Primary data was sourced from respondents based on interviews using questionnaires, which consisted of data: age, education, family history, urinary tract infections, heart disease, diabetes mellitus, hypertension, chronic kidney failure. Meanwhile, secondary data is research supporting data sourced from the health office and other stakeholders. In this research, the sample that became the object of the study was 40 patients with chronic kidney failure who underwent hemodialysis. Sampling uses the total sampling technique. The data of the research results were analyzed by bivariate analysis using the Chi-square test and multivariate analysis by the Multinomial Logistic Regression test. The results of the research showed that the results of epidemiological analysis with chronic kidney failure in patients CKD on HD, age (p value = 0.583), education (p value = 0.583), family history (p value = 0.003), urinary tract infection (p value = 0.024), cardiac history (p value = 0.024), history of diabetes mellitus (p value = 0.038), history of hypertension (p value = 0.022). There was a relationship between family history, urinary tract infection, heart history, history of diabetes mellitus, history of hypertension and chronic kidney failure in patients CKD On HD, and no relationship between age, education and chronic kidney failure in patients CKD on HD.

DNA methylation in peripheral blood is associated with renal aging and renal function decline: a national community study

BackgroundOlder patients are at risk for acute kidney injury and chronic kidney disease. Age-related increases in DNA methylation at CpG islands have been linked to aging-related diseases like cancer and cardiovascular disease, but the exact causal relationship between methylation in renal aging and other kidney diseases remains unclear. This study aimed to elucidate the methylation status of peripheral blood mononuclear cells (PBMCs) in the Asian population. Using human whole blood DNA methylation analysis from the Taiwan Biobank, we included participants with both whole blood genome-wide methylation data and follow-up data on serum creatinine. We investigated hyper- and hypomethylated genes in comparison of participants with higher and lower estimated glomerular filtration (eGFR) decline rate in overall cohort as well as in comparison of old and young participants in subgroup of participants with higher eGFR decline rate. Common genes and signaling pathways in both comparative analyses were identified.ResultsAmong 1587 participants in the analysis, 187 participants had higher eGFR decline rate. According to the comparison of methylation in participants with different eGFR declines and at different ages, respectively, we identified common hypermethylated genes, including DNMT3A and GGACT, as well as hypomethylated genes such as ARL6IP5, CYB5D1, BCL6, RPRD2, ZNF451, and MIAT in both participants with higher eGFR decline and those of older age. We observed associations between the methylation status of signaling pathways and aging as well as renal function decline. These pathways notably included autophagy, p38 mitogen-activated protein kinases, and sirtuins, which were associated with autophagy process and cytokine production.ConclusionsThrough methylation analysis of PBMCs, we identified genes and signaling pathways which could play crucial roles in the interplay of renal aging and renal function decline. These findings contribute to the development of novel biomarkers for identifying at-risk groups and even for therapeutic agent discovery.

Kidney Aging and Chronic Kidney Disease.

The process of aging inevitably leads to an increase in age-related comorbidities, including chronic kidney disease (CKD). In many aspects, CKD can be considered a state of accelerated and premature aging. Aging kidney and CKD have numerous common characteristic features, ranging from pathological presentation and clinical manifestation to underlying mechanisms. The shared mechanisms underlying the process of kidney aging and the development of CKD include the increase in cellular senescence, the decrease in autophagy, mitochondrial dysfunction, and the alterations of epigenetic regulation, suggesting the existence of potential therapeutic targets that are applicable to both conditions. In this review, we provide a comprehensive overview of the common characteristics between aging kidney and CKD, encompassing morphological changes, functional alterations, and recent advancements in understanding the underlying mechanisms. Moreover, we discuss potential therapeutic strategies for targeting senescent cells in both the aging process and CKD.

Association between statin therapy and long-term clinical outcomes in patients with stable coronary disease undergoing percutaneous coronary intervention

This longitudinal cohort study examined the long-term effect of statin therapy on clinical outcomes in patients undergoing percutaneous coronary intervention (PCI). A total of 1760 patients with stable coronary artery disease (CAD) were divided by receipt of statin therapy or not after index PCI. Baseline clinical characteristics, risk factors, angiographic findings, and medications after interventional procedure were assessed to compare long-term clinical outcomes between groups. Predictors for all-cause death and major adverse cardiovascular events (MACE), including myocardial infarction (MI), cardiovascular death, and repeated PCI procedures, were also analyzed. The statin therapy group had higher average serum cholesterol and more elevated low-density lipoprotein cholesterol (LDL-C) than the non-statin therapy group (189.0 ± 47.9 vs 169.3 ± 37.00 mg/dl, 117.2 ± 42.6 vs 98.7 ± 31.8 mg/dl, respectively, both P < 0.001). The non-statin group had higher rates of all-cause death and cardiovascular death compared to statin group (both P < 0.001). After adjustment for age, diabetes, and chronic kidney disease, Cox proportion hazard analysis revealed statin use significantly reduced all-cause death and repeated PCI procedure (hazard ratio: 0.53 and 0.69, respectively). Statin use seemed not reduce the hazard of cardiovascular death or MI in patients with stable CAD after PCI; however, statin therapy still was associated with reduced rates of all-cause death and repeat PCI procedure.

Left atrial wall thickness measured by a machine learning method predicts AF recurrence after pulmonary vein isolation

Abstract Background Left atrial (LA) remodeling plays a significant role in the progression of atrial fibrillation (AF). Although LA wall thickness (LAWT) has emerged as an indicator of structural remodeling, its impact on AF outcomes remains unclear. We aimed to determine the association between LAWT and AF recurrence after pulmonary vein isolation (PVI). Methods Single-center registry of patients enrolled for radiofrequency PVI from 2016 to 2018. In all cases, a pre-ablation CT scan was performed within less than 48 hours. Mean LAWT was retrospectively determined by a semi-automated machine learning method with minimal human intervention (ADAS 3D®). Additionally, regional tissue thickness was assessed in four locations: roof and inferior, posterior, and anterior walls. In a subgroup of patients, a pre-ablation cardiac magnetic resonance (CMR) was also performed within the same week. LA functional parameters and fibrosis, using 3D delayed gadolinium enhancement, were analyzed. The primary endpoint was AF recurrence after a 3-month blanking period. Results A total of 439 patients (mean age 61±12years, 62% male, 78% with paroxysmal AF) were included. The mean LAWT was 1.4±0.2mm (ranging from 0.9 to 1.9mm). Software processing duration was 8.2±0.4 min, and the mean human input time was 1.3±0.1 min. There was no correlation between LAWT and CT-derived LA-indexed volume (Spearman –0.01, p=0.845). During a median follow-up of 5.8 (IQR 4.9–6.6) years, 238 patients (54%) had an AF relapse. LAWT was an independent predictor of recurrence, after adjusting for known confounders including age, non-paroxysmal AF, LA-indexed volume, and chronic kidney disease (adjusted HR 6.49 [95% CI 2.70-15.49], p&amp;lt;0.001). AF recurrence rates were 11%, 15%, and 21%/year across terciles of increasing LAWT (log-rank p&amp;lt;0.001) – Figure. The posterior LAWT revealed the strongest association with the study endpoint (HR 1.93 [95% CI 1.24-3.02], p=0.004). In the cohort of 62 patients with both CT and CMR, LAWT showed weak correlations with LA ejection fraction and LA coupling index (Spearman &amp;lt;0.25; p=0.054 and p=0.093, respectively), and a moderate correlation with LA fibrosis (Spearman 0.468; p&amp;lt;0.001). Conclusions Mean LAWT, easily assessed by commercially available machine learning software, is an independent predictor of AF recurrence after PVI in the long-term follow-up. This association is mainly driven by the posterior LAWT. Whether patients with increased LAWT should receive tailored therapy deserves further investigation.Figure

Mitochondrial calcium uniporter promotes kidney aging in mice through inducing mitochondrial calcium-mediated renal tubular cell senescence.

Renal tubular epithelial cell senescence plays a critical role in promoting and accelerating kidney aging and age-related renal fibrosis. Senescent cells not only lose their self-repair ability, but also can transform into senescence-associated secretory phenotype (SASP) to trigger inflammation and fibrogenesis. Recent studies show that mitochondrial dysfunction is critical for renal tubular cell senescence and kidney aging, and calcium overload and abnormal calcium-dependent kinase activities are involved in mitochondrial dysfunction-associated senescence. In this study we investigated the role of mitochondrial calcium overload and mitochondrial calcium uniporter (MCU) in kidney aging. By comparing the kidney of 2- and 24-month-old mice, we found calcium overload in renal tubular cells of aged kidney, accompanied by significantly elevated expression of MCU. In human proximal renal tubular cell line HK-2, pretreatment with MCU agonist spermine (10 μM) significantly increased mitochondrial calcium accumulation, and induced the production of reactive oxygen species (ROS), leading to renal tubular cell senescence and age-related kidney fibrosis. On the contrary, pretreatment with MCU antagonist RU360 (10 μM) or calcium chelator BAPTA-AM (10 μM) diminished D-gal-induced ROS generation, restored mitochondrial homeostasis, retarded cell senescence, and protected against kidney aging in HK-2 cells. In a D-gal-induced accelerated aging mice model, administration of BAPTA (100 μg/kg. i.p.) every other day for 8 weeks significantly alleviated renal tubuarl cell senescence and fibrosis. We conclude that MCU plays a key role in promoting renal tubular cell senescence and kidney aging. Targeting inhibition on MCU provides a new insight into the therapeutic strategy against kidney aging.

#2330 Fisetin supplement ameliorates aging related changes in the kidney

Abstract Background and Aims As the ageing population continues to grow worldwide, aging-related diseases are becoming an excessive burden on the global healthcare system. The kidney is one of the organs most affected by aging, which undergoes changes of decreased glomerular filtration rate (GFR), alterated renal blood flow, increased inflammation and fibrosis that increase the susceptibility to developing acute kidney injury (AKI) and chronic kidney disease (CKD). To date, the mechanisms underlying the changes of aged kidneys has not been fully elucidated and therapeutic strategies are still under exploration. Fisetin is a natural flavonol that has been shown to be beneficial to many age-related disorders, as well as increase lifespan in preclinical animal models. However, whether and how fisetin protects against kidney aging remains unclear. In the present study, we assessed the efficacy of fisetin as a senolytic to reduce cell senescence and SASP factors and improve renal function in old mice. Method 18 month-old C57BL/6 mice were randomly divided into the model group (n = 6), the fisetin low-dose group (100 mg/kg/d B.W., n = 6), fisetin high-dose group (100 mg/kg/d B.W., n = 6) and the rapamycin group (14 ppm, positive control, n = 6). The control group (n = 6) was composed of wild-type C57BL/6 mice of 4 month age. The fisetin and rapamycin were given in the diet for 4 months. Mice of model and treatment group were sacrificed at the age of 22 month and the blood and kidney samples were collected. The GFR of mice in each group was detected and the pathological morphology, lipid accumulation, collagen deposition of the kidneys were assessed. Additionally, the expressions of senescence markers including p53, p21,p16, and SASPs within the kidneys were analyzed. Results Fisetin treatment effectively restored the decline in GFR of old mice. Moreover, administration with fisetin significantly reduced age-related pathology including lipid accumulation and collagen fiber deposition in mice kidneys. The expression of aging markers of p53, p21,p16 and SASPs was remarkably upregulated in the kidneys of model mice, which was suppressed by fisetin treatment. Moreover, the kidney inflammation and oxidative stress as observed in aged kidneys was alleviated in mice of fisetin treatment group. Conclusion The natural product fisetin has senotherapeutic activity in mice kidneys. Intervention with fisetin is a promising therapy for clinical translation to target excess cell senescence to treat age-related kidney dysfunction.

#2717 Fermentable and viscous dietary fiber types improve cortical bone in a rat model of chronic kidney disease-mineral and bone disorder

Abstract Background and Aims Renal osteodystrophy is highly prevalent among people with chronic kidney disease (CKD). We recently showed that inulin, a prebiotic fermentable dietary fiber, improved cortical bone parameters in rats with moderate-to-severe CKD. Our objective was to evaluate if this effect was unique to the prebiotic fibers or if other fiber properties, such as viscosity, could be beneficial to bone in a rat model of CKD-mineral and bone disorder (CKD-MBD). Method 22-week-old Cy/+ male rats (50% kidney function compared to normal; CKD hereafter) were randomly assigned to receive one of four fiber treatments (10% w/w each) based on fermentability and viscosity: 1) Cellulose (−fermentability, −viscosity), 2) Inulin (+fermentability, −viscosity), 3) Psyllium husk (−fermentability, +viscosity), or 4) Pectin (+ fermentability, +viscosity). These diets were formulated with a semi-purified, casein-based background diet with 0.7% calcium and 0.7% phosphorus. Treatments lasted 10 weeks, and rats were euthanized at 32 weeks of age (kidney failure; ∼15% of normal). Micro-computed tomography (μCT) at 12-μm resolution was performed on the proximal tibia. Serum creatinine, plasma phosphorus, and plasma calcium were analyzed using colorimetric assays. One-way ANOVA was used to test the effect of dietary fiber types on outcome measures. Results At 32 weeks of age, serum creatinine was lower in the inulin, psyllium, and pectin-treated CKD rats (&amp;lt;0.04). Plasma calcium concentrations were similar between treatments, but phosphorus was lower in the psyllium and pectin-treated CKD rats (p &amp;lt; 0.02). Bone cortical area was higher in the inulin and psyllium-treated CKD rats compared to cellulose-treated rats (p &amp;lt; 0.007). Cortical thickness was higher in the inulin, psyllium, and pectin-treated CKD rats compared to cellulose-treated rats (p &amp;lt; 0.02). There was less cortical porosity in the inulin, psyllium, and pectin-treated rats (p &amp;lt; 0.02). Fermentable or viscous fibers did not impact trabecular bone volume, thickness, spacing, and number (p &amp;lt; 0.05). Plasma phosphorus was negatively associated with cortical area (r = −0.56; p &amp;lt; 0.0001) and cortical thickness (r = −0.75; p &amp;lt; 0.0001), and positively associated with cortical porosity (r = 0.74; p &amp;lt; 0.0001). Conclusion Fermentable and viscous fibers improved cortical bone but had no effect on trabecular bone. This effect may be, at least in part, due to the fiber's ability to lower plasma phosphorus and likely parathyroid hormone.

#325 Prescribing patterns in older people with advanced chronic kidney disease approaching the end of life

Abstract Background and Aims Advancing age and chronic kidney disease (CKD) are risk factors for polypharmacy—the regular daily intake of &amp;gt;5 medications. Polypharmacy is a key action area for the World Health Organization in its effort to reduce global medication-related harm. Deprescribing, the systematic review and rationalisation of potentially inappropriate medications, is a proposed way of addressing polypharmacy. Deprescribing is particularly relevant near the end of life, when preventative treatments provide less benefit. Prescribing practices for elderly people with advanced CKD in the last years of life are currently unknown. The aim of this study was to describe prescribing and deprescribing patterns in such a cohort. Method The EQUAL study [1] is an international, prospective cohort study of people ≥65 years with an incident estimated glomerular filtration rate (eGFR) of ≤20 ml/min/1.73 m2. We analysed data from participants who died during follow up, including 3-6 monthly study-visit-collected prescribed oral medications (POMs). Generalized additive models were used to explore trends leading up to death in the total number of POMs, and the proportion of participants taking specific medications. Data are presented for medications: a) identified as targets for deprescribing in the elderly with CKD (statins, proton-pump inhibitors (PPIs) and antihypertensives—alpha-blockers, beta-blockers, calcium-channel blockers (CCBs), diuretics and renin-angiotensin-aldosterone inhibitors (RAASis)); b) used for symptom control in kidney failure (opioids and gabapentinoids); and c) prescribed to &amp;gt;30% of the cohort (allopurinol, aspirin, vitamin D). Results Data from 563 participants were analysed, comprising 2793 study visits (median follow-up time 2.2 years (interquartile range (IQR) 1.1-3.8) pre-death), and 22,200 POMs. At baseline, mean age was 77.8 years (standard deviation (SD) 6.7), median eGFR 18.1 mls/min/1.73 m2 (IQR 15.0-21.2), and 87.2% were experiencing polypharmacy. The number of POMs increased over the time approaching death (Fig. 1)—7.3 (95% confidence interval (CI) 6.9-7.7) at 5 years pre-death, 8.3 (95% CI 8.0-8.6) at 2.5 years pre-death, and 8.7 (95% CI 8.4-9.1) at death. At their final study visit 90.1% were experiencing polypharmacy. Trends in the proportion of individuals prescribed specific medications differed by POM class (Fig. 2). Opioids, diuretics and PPIs increased in the last years of life; statins, RAASis, alpha-blockers and CCBs decreased; and allopurinol, beta-blockers and gabapentinoids remained stable. Aspirin and vitamin D showed phasic patterns, increasing then decreasing. Conclusion Elderly people with advanced CKD experience increasing levels of polypharmacy as they approach the end of life. Although there is evidence that certain medication classes are being deprescribed, this is outweighed by increased prescribing of other agents. Previous analyses of EQUAL decedents have shown that blood pressure decreases pre-death—we show this is despite reductions in most classes of antihypertensives. Our work suggests a high reliance upon pharmacological interventions (both symptom-directed and preventative) for older people with CKD who are approaching death. We cannot ascertain whether this reflects personalised prescribing, aligned with individuals’ preferences and prognoses; however, high levels of polypharmacy potentiate risks of side effects, medication burden and drug-drug interactions, and indicate a role for enhanced medication review in this setting.

#363 Altered filtration of middle-sized molecules is related to cardiovascular disease-related proteins

Abstract Background and Aims Cardiovascular (CV) complications, driven by complex vascular-metabolic interactions, are the leading cause of frailty in chronic kidney disease (CKD) complications. Advancing knowledge on cardio-renal interactions is a key to preventive and treatment strategies. Still, the cost-effective tools and biomarkers for early detection of altered glomerular filtration that subsequently leads to accelerated cardiovascular aging and, thus, higher CV mortality are lacking. Our objective was to investigate how molecules of varying masses, specifically cystatin C and creatinine, are filtered in kidney in relation to variations of plasma protein levels that might accelerate vascular changes, ultimately leading to early vascular aging and chronic kidney disease (CKD). Method From the Malmo Diet Cancer cohort, 4426 out of the 5061 participants had cardiovascular and renal biomarkers measured (mean age of 57 ± 6 years). These biomarkers included factors related to tissue growth and repair (EGFR), matrix metalloproteinases (MMP-12), proinflammatory cytokines (TNF-R1, TNF-R2, CXCL13, CXCL5), markers of vascular repair (SCF), homeostatic cytokines (CCL19), anti-apoptotic proteins (REG-4), adipokines (FABP4, LEP), as well as other cardiovascular proteins (NT-pro-BNP, MB) and indicators of kidney function. These 13 proteins were analyzed using multiplex proximity extension assay (Olink Cardiovascular II and Oncology panels), and have molecular masses either like creatinine (0.113 kDa) or cystatin C (13.3 kDa). These proteins were previously shown to be associated with measured glomerular filtration rate (mGFR) by Christensson A et al. (Proteomics Clin App, 2018). Kidney function was estimated by using cystatin C (CAPA, CKD-EPIcys) and creatinine (Lund-Malmo revised, CKD-EPIcr) equations. The filtration ratio was presented as CAPA/LMrev and CKD-EPIcys/CKD-EPIcr. The subgroups of this ratio were &amp;lt;0.70. Results Mean kidney function was as follows: 65 (±15)/ 69 (±16)/ 78 (±13) and 76 (±14) mL/min/1.73 m2 (CAPA/ CKD-EPIcys/ LMrev and CKD-EPIcr, respectively). The CAPA/LMrev filtration ratio was 0.84 (±0.18), whereas CKD-EPIcys/cr was 0.91 (±0.19). The filtration ratio negatively correlated with TNF-R1, TNF-R2, SCF, MMP-12, FABP4, LEP, NT-pro-BNP, CCL19, CXCL5, CXCL13 and REG-4; positively to EGFR and MB (all p &amp;lt; 0.001). In the whole cohort, participants with filtration ratio below 0.7 had significantly higher levels of TNF-R1, TNF-R2, MMP12, FABP4, LEP, NT-pro-BNP, CCL19, REG-4, and CXCL13, but similar levels of EGFR. CXCL5 and SCF levels were higher at &amp;lt;0.70 compared to 0.84-0.99 and &amp;gt;1.0 (Fig. 1). Interestingly, in women, MB was highest at &amp;lt;0.70; SCF level was higher at &amp;lt;0.70 compared to 0.84-0.99 and &amp;gt;1.00; EGFR level was highest at 0.70-0.84 compared to 0.84-0.99. In men, higher FABP4, LEP, CCL19, and MB were observed at &amp;lt;0.70 compared to 0.84-0.99 and &amp;gt;1.00. Conclusion Altered glomerular filtration for middle-sized molecules is related to the accumulation of plasma proteins that have similar molecular mass to creatinine and cystatin C and have sex-specific patterns. The proteins studied have been previously shown to contribute to vascular aging, cardiac damage and remodeling, and chronic kidney disease, and thus enlighten complex mechanisms behind cardio-renal interactions.

Implications of Five Different Risk Models In Primary Prevention Guidelines.

A lack of consensus exists across guidelines as to which risk model should be used for the primary prevention of cardiovascular disease (CVD). Our objective was to determine potential improvements in the number needed to treat (NNT) and number of events prevented (NEP) using different risk models in patients eligible for risk stratification. A retrospective observational cohort was assembled from primary care patients in Ontario, Canada between January 1st, 2010, to December 31st, 2014 and followed for up to 5 years. Risk estimation was undertaken in patients 40-75 years of age, without CVD, diabetes, or chronic kidney disease using the Framingham Risk Score (FRS), Pooled Cohort Equations (PCEs), a recalibrated FRS (R-FRS), Systematic Coronary Risk Evaluation 2 (SCORE2), and the low-risk region recalibrated SCORE2 (LR-SCORE2). The cohort consisted of 47,399 patients (59% women, mean age 54). The NNT with statins was lowest for SCORE2 at 40, followed by LR-SCORE2 at 41, R-FRS at 43, PCEs at 55, and FRS at 65. Models that selected for individuals with a lower NNT recommended statins to fewer, but higher risk patients. For instance, SCORE2 recommended statins to 7.9% of patients (5-year CVD incidence 5.92%). The FRS, however, recommended statins to 34.6% of patients (5-year CVD incidence 4.01%). Accordingly, the NEP was highest for the FRS at 406 and lowest for SCORE2 at 156. Newer models such as SCORE2 may improve statin allocation to higher risk groups with a lower NNT but prevent fewer events at the population level.

Tubular CPT1A deletion minimally affects aging and chronic kidney injury.

Tubular CPT1A deletion minimally affects aging and chronic kidney injury.

Association between hyperuricemia and the risk of mortality in patients with osteoarthritis: A study based on the National Health and Nutrition Examination Survey database.

The purpose of this study was to evaluate the relationship between hyperuricemia and the risks of all-cause mortality and cardiovascular disease (CVD) mortality in patients with osteoarthritis (OA). A retrospective cohort study was performed on 3,971 patients using data from the National Health and Nutrition Examination Survey database between 1999 and 2018. OA was diagnosed through specific questions and responses. The weighted COX regression models were used to explore the factors associated with all-cause mortality/CVD mortality in OA patients. Subgroup analyses were conducted based on age, gender, hypertension, dyslipidemia, CVD, and chronic kidney disease (CKD). Hazard ratio (HR) and 95% confidence interval (95% CI) were measured as the evaluation indexes. During the duration of follow-up time (116.38 ± 2.19 months), 33.69% (1,338 patients) experienced all-cause mortality, and 11.36% (451 patients) died from CVD. Hyperuricemia was associated with higher risks of all-cause mortality (HR: 1.22, 95% CI: 1.06-1.41, P = 0.008) and CVD mortality (HR: 1.32, 95% CI: 1.02-1.72, P = 0.036) in OA patients. Subgroup analyses showed that hyperuricemia was related to the risk of all-cause mortality in OA patients aged >65 years (HR: 1.17, 95% CI: 1.01-1.36, P = 0.042), in all male patients (HR: 1.41, 95% CI: 1.10-1.80, P = 0.006), those diagnosed with hypertension (HR: 1.17, 95% CI: 1.01-1.37, P = 0.049), dyslipidemia (HR: 1.18, 95% CI: 1.01-1.39, P = 0.041), CVD (HR: 1.30, 95% CI: 1.09-1.55, P = 0.004), and CKD (HR: 1.31, 95% CI: 1.01-1.70, P = 0.046). The association between hyperuricemia and a higher risk of CVD mortality was found in OA patients aged ≤ 65 years (HR: 1.90, 95% CI: 1.06-3.41, P = 0.032), who did not suffer from diabetes (HR: 1.36, 95% CI: 1.01-1.86, P = 0.048), who did not suffer from hypertension (HR: 2.56, 95% CI: 1.12-5.86, P = 0.026), and who did not suffer from dyslipidemia (HR: 2.39, 95% CI: 1.15-4.97, P = 0.020). These findings emphasize the importance of monitoring serum uric acid levels in OA patients for potentially reducing mortality associated with the disease.

Patient Selection for Active Surveillance for Small Renal Masses: A Systematic Review of the Literature

BACKGROUND: The role of active surveillance (AS) has been recognized as a management strategy for localized small renal masses (SRMs). The EAU guidelines suggest AS can be offered to frail and/or comorbid patients diagnosed with SRM due to the low cancer-specific-mortality (CSM) and higher competing-cause mortality. As specific cut-offs defining the characteristics of frail and comorbid patients who may benefit from AS remain less clear, our objective is to conduct a systematic review aiming to identify potential characteristics that could assist physicians in shared decision-making. METHODS: The systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Two authors independently screened the literature according to the PICOs criteria previously outlined in our registered review protocol (via Pubmed, Embase, and the Cochrane Central Register of Controlled Trials), extracted data, and assessed the risk of bias, using Newcastle-Ottawa Scale. Studies that analyzed differences in patient’s tumor-related and molecular characteristics associated with any differences in growth rate (GR), overall survival (OS), cancer-specific survival (CSS), and metastasis-free survival (MFS), were considered eligible. RESULTS: Nineteen studies comprising a total of 5105 patients were analyzed. Patient-specific factors such as age and cardiovascular index, which demonstrated a predominant impact on OS, exhibited a high degree of consistency across the analyzed studies. Less concordance was found when exploring GR, with the main predictors being ethnicity, age, sex, comorbidity, symptoms, and eGFR. The analysis of tumor-related characteristics, such as tumor size, nephrometry score, and mass histology, among others, yielded contradictory outcomes concerning their impact on GR and CSS. CONCLUSION: Age, cardiovascular index, and chronic kidney disease have shown to be reliable predictors of OS. Nonetheless, significant debates persist regarding tumor characteristics or molecular markers that may influence survival and GR. Further research is awaited to shed light on the potential to identify prognostic factors. This would aid in pinpointing the subgroup of patients who could experience additional benefits from AS, potentially leading to a reduced risk of progression. It is imperative to standardize approaches to AS and reporting of results, as this will be pivotal for future quantitative analyses.

ZFYVE21 promotes endothelial nitric oxide signaling and vascular barrier function in the kidney during aging

ZFYVE21 is an ancient, endosome-associated protein that is highly expressed in endothelial cells (ECs) but whose function(s) invivo are undefined. Here, we identified ZFYVE21 as an essential regulator of vascular barrier function in the aging kidney. ZFYVE21 levels significantly decline in ECs in aged human and mouse kidneys. To investigate attendant effects, we generated EC-specific Zfyve21-/- reporter mice. These knockout mice developed accelerated aging phenotypes including reduced endothelial nitric oxide (ENOS) activity, failure to thrive, and kidney insufficiency. Kidneys from Zfyve21 EC-/- mice showed interstitial edema and glomerular EC injury. ZFYVE21-mediated phenotypes were not programmed developmentally as loss of ZFYVE21 in ECs during adulthood phenocopied its loss prenatally, and a nitric oxide donor normalized kidney function in adult hosts. Using live cell imaging and human kidney organ cultures, we found that in a GTPase Rab5- and protein kinase Akt-dependent manner, ZFYVE21 reduced vesicular levels of inhibitory caveolin-1 and promoted transfer of Golgi-derived ENOS to a perinuclear Rab5+ vesicular population to functionally sustain ENOS activity. Thus, our work defines a ZFYVE21- mediated trafficking mechanism sustaining ENOS activity and demonstrates the relevance of this pathway for maintaining kidney function with aging.