Onset Of Chronic Kidney Disease Research Articles

516 SAFETY OF PCSK9I IN A SINGLE COUNTRY, MULTICENTER, OBSERVATIONAL STUDY: A POST-HOC ANALYSIS OF THE AT-TARGET-IT STUDY

Abstract Introduction PCSK9 inhibitors (PCSK9i) significantly decrease LDL cholesterol (LDL-C), either as monotherapy or in addition to the maximally tolerated dose of statin and/or ezetimibe. Yet, few data are available in real-world observations. Purpose AT-TARGET-IT is an Italian multicenter registry involving 9 Italian centers, designed to assess efficacy, adherence, and persistence of PCSK9i, as well as prescribing doctors’ behavior in patients with atherosclerotic cardiovascular disease (ASCVD) or familial hypercholesterolemia (FH). The aim of the present analysis was to assess differences between evolocumab and alirocumab on safety in patients on PCSK9i in a real-world single country observational study. Methods From June through November 2021, we enrolled patients with PCSK9i first prescription from 6 months before inclusion through starting of PCSK9i use. Clinical and demographic characteristics, concomitant therapies, blood chemistry, were recorded at the time of first prescription and at the latest observation preceding inclusion in the study. Results Of 798 patients enrolled, 566 (70.9%) patients took Evolocumab and 232 (29.1%) Alirocumab (of them, 117 patients Alirocumab 75 mg and 115 Alirocumab 150 mg). The LDL-C values reductions did not significantly differ between Evolocumab and Alirocumab groups (65.1% for Evolocumab; 64.5% for Alirocumab, p=ns). Regarding safety events, after a median observation period of 19.3 months (6; 57), 19 patients (2.4%) had acute coronary syndrome, 18 (2.3%) hospitalization for CV causes, 3 (0.4%) stroke, 6 (0.8%) new-onset heart failure (HF) and 68 (4.9%) the composite endpoints of ACS, CV hospitalization, new onset HF, new onset chronic kidney disease, stroke and cerebrovascular insufficiency. Comparing events between patients in Alirocumab and in Evolocumab, no significant difference was found between the two groups. Combined endpoint of adverse events occurred more frequently in patients in Alirocumab (27; 11.6%), in comparison with those in Evolocumab (41; 7.2%) (p=0.044) (Figure). Conclusion AT-TARGET-IT study shows that between evolocumab and alirocumab there was a statistically significant difference on the combined endpoint of adverse events.

Rationale for the evaluation of renal functional reserve in allogeneic stem cell transplantation candidates: a pilot study.

The main purpose of our study was to evaluate the ability of renal functional reserve (RFR) to stratify the risk of acute kidney injury (AKI) occurrence within 100 days of hematopoietic stem cell transplantation (HSCT) and to predict any functional recovery or the onset of chronic kidney disease. A secondary aim was to identify the clinical/laboratory risk factors for the occurrence of AKI. The study design is prospective observational. We enrolled 48 patients with normal basal glomerular filtration rate (bGFR) who underwent allogenic HSCT. A multiparameter assessment and the Renal Functional Reserve Test (RFR-T) using an oral protein load stress test were performed 15 days before the HSCT. Different RFRs corresponded to the same bGFR values. Of 48 patients, 29 (60%) developed AKI. Comparing the AKI group with the group that did not develop AKI, no statistically significant difference emerged in any characteristic related to demographic, clinical or multiparameter assessment variables except for the estimated GFR (eGFR). eGFR ≤100mL/min/1.73 m2 was significantly related to the risk of developing AKI (Fisher's exact test, P=.001). Moreover, RFR-T was lower in AKI+ patients vs AKI- patients, but did not allow statistical significance (28% vs 40%). In AKI patients, RFR >20% was associated with complete functional recovery (one-sided Fisher's exact test, P=.041). The risk of failure to recover increases significantly when RFR ≤20% (odds ratio=5.50, 95% confidence interval = 1.06-28.4). RFR identifies subclinical functional deterioration conditions essential for post-AKI recovery. In our cohort of patients with no kidney disease (NKD), the degree of pre-HSCT eGFR is associated with AKI risk, and a reduction in pre-HSCT RFR above a threshold of 20% is related to complete renal functional recovery post-AKI. Identifying eGFR first and RFR second could help select patients who might benefit from changes in transplant management or early nephrological assessment.

Identification of ferroptosis‑associated genes in chronic kidney disease.

Ferroptosis serves a pivotal role in developing chronic kidney disease (CKD). The present study aimed to detect and confirm the relevance of potential ferroptosis-related genes in CKD using bioinformatics and experimentation strategies. The original GSE15072 mRNA expression dataset was retrieved from the Gene Expression Omnibus database. Subsequently, the potential differentially expressed genes associated with ferroptosis of CKD were screened using R software. Gene Ontology (GO) and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway enrichment analyses, correlation analysis and protein-protein interactions (PPI) were performed for differentially expressed ferroptosis-associated genes (DFGs). Lastly, the expression levels of the top nine DFGs were measured in the kidney tissue of Adriamycin-induced CKD rats and healthy controls via reverse transcription-quantitative (RT-q)PCR analysis. Overall, 49 DFGs among 21 patients with CKD and nine healthy controls were identified. GO and KEGG enrichment analyses demonstrated that these DFGs were primarily involved in 'ferroptosis' and 'mitophagy'. PPI findings indicated that these ferroptosis-associated genes interacted with one another. RT-qPCR of CKD tissue from the rat model revealed that STAT3, MAPK14, heat shock protein (HSP)A5, MTOR and solute carrier family 2 member 1 (SLC2A1) mRNA levels in CKD were upregulated. Overall, 49 potential ferroptosis-associated genes of CKD were identified via bioinformatics analyses. STAT3, MAPK14, HSPA5, MTOR and SLC2A1 may influence CKD onset by regulating ferroptosis. The present results add to the existing body of knowledge about CKD and may be useful in the treatment of CKD.

Low birth weight, nephron number and chronic kidney disease

Chronic kidney diseases have a significant impact on morbidity and mortality worldwide. Low birth weight, fetal growth restriction and prematurity are indicators of fetal growth and development disorders associated with a congenital reduction in nephron number, which predisposes to an increased risk for chronic kidney disease. On an individual basis, a small nephron number at birth is not always enough to determine the onset of chronic kidney disease, but it decreases the ability of the kidneys to resist any insults to renal tissue that may occur later in life, such as exposure to nephrotoxic drugs or episodes of acute kidney injury. The high incidence of low birth weight and preterm birth globally suggests that, at the population level, the impact of alterations in fetal development on the subsequent onset of chronic kidney disease could be significant. The implementation of strategies aimed at reducing the incidence of prematurity, fetal growth restriction, as well as other conditions that lead to low birth weight and a reduced nephron number at birth, provides an opportunity to prevent the development of chronic kidney disease in adulthood. For these purposes the coordinated intervention of several specialists, including obstetricians, gynecologists, neonatologists, nephrologists, and family doctors, is necessary. Such strategies can be particularly useful in resource-poor countries, which are simultaneously burdened by maternal, fetal and child malnutrition; poor health; epidemics caused by communicable diseases; and little access to screening and primary care.

Abstract 11834: Ability of Machine Learning Algorithms to Predict Chronic Kidney Disease Using Health Examination Data From the Japanese General Population

Introduction: There is a large amount of specific health examination data in Japan. Efforts to utilize these data to predict the future onset of cardiovascular diseases are important from the perspective of improving prognosis and QOL as well as medical economy. We evaluated the prediction ability of machine learning algorithms for newly developed 5-year chronic kidney disease (CKD). Methods: Among those who underwent examinations from 2008 to 2018, individuals whose baseline (year X), 1 year later (year X+1), and 5 years later (year X+5) data were available were included. CKD was defined as estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2. Those with CKD in year X or X+1 were excluded. Three different machine learning algorithms, Random Forrest (RF), Logistic Regression (LR), and Multilayer Perceptron (MLP) to predict CKD on year X+5 from single-year data (year X) or consecutive 2 years data (year X and X+1) were assessed, and the predictive ability was compared. Anthropometric measurements, blood pressure and pulse rate, laboratory measurements, and lifestyle related indices were included as explanatory variables. Results: A total of 43,084 participants (age 53.7±10.1 years, male 49.9%) were included and 2,928 individuals (6.8%) had CKD in year X+5. The indices of predictive ability from single-year data were as follows: RF, AUC 0.88, accuracy 0.93, recall 0.99, precision 0.93; LR, AUC 0.89, accuracy 0.93, recall 0.99, precision 0.94; MLP, AUC 0.89, accuracy 0.93, recall 0.99, precision 0.93. Those from multi-year data were as follows: RF, AUC 0.93, accuracy 0.95, recall 0.99, precision 0.95; LR, AUC 0.90, accuracy 0.97, recall 0.99, precision 0.97; MLP, AUC 0.89, accuracy 0.97, recall 0.99, precision 0.97. The variables with the highest importance features were serum creatinine (0.41), age (0.13), medication for hypertension (0.04), and systolic blood pressure (0.03). Conclusions: The ability to predict new onset of CKD was better when using data from two consecutive years than when using data from a single year. The AUCs ranged from 0.89 to 0.93 and were generally better than previously reported risk models using statistical methods. Serum creatinine levels, along with age and blood pressure have been identified as major contributors.

Risk factors for neurocognitive impairment and the relation with structural brain abnormality in children and young adults with severe chronic kidney disease

BackgroundSevere chronic kidney disease (CKD) in children and young adults has shown to be associated with abnormal brain development, which may contribute to neurocognitive impairments. We aimed to investigate risk factors for neurocognitive impairment and investigate the relation with structural brain abnormalities in young severe CKD patients.MethodsThis cross-sectional study includes 28 patients with severe CKD (eGFR < 30), aged 8–30 years (median 18.5 years), on different treatment modalities (pre-dialysis [n = 8], dialysis [n = 8], transplanted [n = 12]). We assessed neurocognitive functioning using a comprehensive test battery and brain structure by magnetic resonance imaging metrics of brain volume and white matter integrity (fractional anisotropy [FA] and mean diffusivity [MD] measured with diffusion tensor imaging). Multivariate regression and mediation analyses were performed between clinical CKD parameters, brain structure, and neurocognitive outcome.ResultsA combination of risk factors (e.g., longer time since kidney transplantation, longer dialysis duration and late CKD onset) was significantly associated with lower intelligence and/or worse processing speed and working memory. Lower FA in a cluster of white matter tracts was associated with lower intelligence and mediated the relation between clinical risk factors and lower intelligence.ConclusionsYoung severe CKD patients with a prolonged duration of kidney replacement therapy, either dialysis or transplantation are at particular risk for impairments in intelligence, processing speed, and working memory. Disrupted white matter integrity may importantly contribute to these neurocognitive impairments. Prospective, longitudinal studies are needed to elucidate the mechanisms involved in CKD and treatment that affect white matter integrity and neurocognitive outcome in young patients.Graphical abstractA higher resolution version of the Graphical abstract is available as Supplementary information

Coding Variants of the FMO3 Gene Are Associated with the Risk of Chronic Kidney Disease: A Case-Control Study.

Chronic kidney disease (CKD) is a global health concern involving roughly one-tenth of developed countries' populations. The flavin-containing dimethylaniline monooxygenase 3 (FMO3) gene encodes an enzyme that catalyzes trimethylamine N-oxide (TMAO), a toxin in CKD sufferers. This preliminary study aims to evaluate the association between coding region variations of FMO3, rs2266782G/A (E158K), rs2266780A/G (E308G), and rs1736557G/A (V257M), and the susceptibility to CKD. A total of 356 participants were enrolled, including 157 patients diagnosed with CKD and 199 age-matched healthy individuals. Genotyping of FMO3 gene variations was performed via PCR-RFLP and ARMS-PCR methods. Our findings revealed a significant association between rs2266780A/G and rs1736557G/A and CKD under different genetic models. Compared to the GGG haplotype of rs2266782/rs1736557/rs2266780, the GAG, GAA, AAG, and AAA haplotype combinations conferred an increased risk of CKD in our population. Interaction analysis revealed that some genotype combinations, including GA/AA/AA, AA/AA/AA, GA/AA/GA, and GG/AG/AA, dramatically increased CKD risk in the Iranian population. No correlation was found between FMO3 polymorphisms and CKD stages. These observations highlight the potential impact of coding variants of the FMO3 gene on the onset of CKD. Further investigations into expanded populations and diverse races are needed to confirm our findings.

Long term outcomes of bevacizumab-associated kidney adverse effects

Bevacizumab is an anti-angiogenic monoclonal antibody against vascular endothelial growth factor (VEGF) and has multiple indications with known renal adverse effects, notably proteinuria, and acute kidney injury (AKI). There is insufficient knowledge about the long-term outcomes of its renal adverse effects. In this retrospective study, we reviewed the clinical course of all patients who received bevacizumab and developed therapy associated AKI, chronic kidney disease (CKD), or proteinuria. Among the 1,506 patients who received bevacizumab, the renal events attributed to bevacizumab were: 125 episodes of AKI (8.3%), 110 new-onset proteinuria events (7.3%), and new onset CKD in 112 patients (7.4%). All patients with bevacizumab-associated AKI recovered without requiring renal replacement therapy and in most patients (59%), the renal function returned to baseline. In conclusion, bevacizumab associated renal adverse effects were a common occurrence but with minimal long term adverse outcomes considering that this population is significantly impacted by their cancer prognosis. These results are helpful during counseling regarding risks and benefits of therapy discontinuation in patients who develop bevacizumab-associated adverse effects.

Age-Related Association between Multimorbidity and Mortality in US Veterans with Incident Chronic Kidney Disease

Introduction: Mortality is an important long-term indicator of the public health impact of chronic kidney disease (CKD). We investigated the role of individual comorbidities and multimorbidity on age-specific mortality risk among US veterans with new-onset CKD. Methods: The cohort included 892,005 veterans aged ≥18 years with incident CKD stage 3 between January 2004 and April 2018 in the US Veterans Health Administration (VHA) system and followed until death, December 2018, or up to 10 years. Incident CKD was defined as the first-time estimated glomerular filtration rate (eGFR) was <60 mL/min/1.73 m² for >3 months. Comorbidities were ascertained using inpatient and outpatient clinical records in the VHA system and Medicare claims. We estimated death rates for any cardiovascular disease (CVD, a composite of 6 CVD conditions) and 15 non-CVD comorbidities, and adjusted risks of death (hazard ratio [HR], 95% confidence interval [CI]) overall and by age group at CKD incidence. Results: At CKD incidence, the mean age was 72 years, and 97% were male; the mean eGFR was 52 mL/min/1.73 m², and 95% had ≥2 comorbidities (median, 4) in addition to CKD. During a median follow-up of 4.5 years, among the 16 comorbidities, CVD was associated with the highest relative risk of death in younger veterans (HR 1.96 [95% CI: 1.61–2.37] in ages 18–44 years and HR 1.66 [1.63–1.70] in ages 45–64 years). Dementia was associated with the highest relative risk of death among older veterans (HR 1.71 [1.68–1.74] in ages 65–84 years and HR 1.69 [1.65–1.73] in ages 85–100 years). The additive effect of multimorbidity on risk of death was stronger in younger than older veterans. Compared to having 1 or no comorbidity at CKD onset, the risk of death with ≥5 comorbidities was >7-fold higher among veterans aged 18–44 years and >2-fold higher among veterans aged 85–100 years. Conclusion: The large burden of comorbidities in US veterans with newly identified CKD places them at the risk of premature death. Compared with older veterans, younger veterans with multiple comorbidities, particularly with CVD, at CKD onset are at an even higher relative risk of death.

169 Establishing Reliable Detection and Follow–up of Newly Diagnosed Chronic Kidney Disease in Emergency Department Patients

Early detection and follow–up of chronic kidney disease (CKD) is important for management and to minimize disease progression. Since the first signal of new–onset CKD can occur during emergency department (ED) encounters, the purpose of this study was to determine the number of ED patients with abnormally low estimated glomerular filtration rates (eGFRs) who were at risk for progression to CKD and to develop workflows to help connect these patients to appropriate follow–up.

Kidney Function Trajectory within Six Months after Acute Kidney Injury Inpatient Care and Subsequent Adverse Kidney Outcomes: A Retrospective Cohort Study.

Timing and extent of kidney function recovery after an acute kidney injury (AKI) episode are associated with chronic kidney disease onset and progression. This study aimed to categorize AKI recovery patterns within 6 months after index hospital discharge and associate them with kidney outcomes. This was a retrospective cohort study of 234,867 patients, hospitalized between 2010 and 2017, and classified as AKI or no AKI. Kidney function recovery from pre-hospitalization baseline within 1.5× serum creatinine (SCr) were evaluated at 3 and 6 months after hospital discharge and categorized as persistent non-recovery (PNR: SCr not recovered at 3 and 6 months), non-recovery (NR: SCr not recovered at 6 months), and recovery (SCr recovered at 6 months). A composite of incident chronic kidney disease, kidney replacement therapy, and estimated glomerular filtration rate reduction >30% from baseline and <15 mL/min/1.73 m2 was evaluated. Of 14,673 AKI surviving patients, 10.18% had PNR and 14.33% showed NR. Compared with no AKI, PNR and NR of AKI were associated with an increased risk of composite adverse outcomes (adjusted subdistribution hazard ratio (SHR) 4.55; 95% CI, 4.05–5.11; SHR, 3.54; 95% CI, 3.18–3.94, respectively). Patients with NR showed a greater risk of adverse outcomes than those with non-rapid recovery at 3 months after hospital discharge. The AKI recovery pattern within 6 months following inpatient care revealed an increasing continuum of risk of long-term adverse kidney outcomes. Risk stratification and a kidney function monitoring plan at discharge are needed to improve post-AKI care.

Impact of hypertension and diabetes on the onset of chronic kidney disease in a general Japanese population.

Hypertension (HT) and diabetes mellitus (DM) are both major risk factors for chronic kidney disease (CKD); however, few studies have examined the impacts of the combination of HT and DM on CKD development in general populations. We aimed to explore whether HT or DM contributes more to CKD development in a Japanese community. A total of 5823 individuals without a history of CKD who underwent specific health checkups in fiscal year 2013 were monitored until the end of March 2018. Participants were categorized as having neither HT nor DM (none group), either HT or DM, and both (HT + DM). We calculated the hazard ratios (HRs) for developing CKD in each category using Cox proportional hazards models after adjusting for age, dyslipidemia, smoking, and alcohol drinking and with the none group as the reference. We also estimated the population attributable fraction (PAF) for CKD development in populations with either HT or DM or both. During a mean follow-up of 3.0 years, 759 individuals developed CKD, with HRs of 1.56 with a 95% confidence interval (CI) [1.33, 1.83], 1.22 with a 95% CI [0.86, 1.75], and 2.83 with a 95% CI [2.22, 3.63] for the HT only, DM only and HT + DM categories, respectively. Sex-specific analysis showed similar findings. The PAFs for CKD (14.1% and 17.2% for men and women, respectively) were the highest among participants with HT only. We concluded that in this Japanese community, HT contributed more than DM to CKD development; hence, managing hypertension is important to prevent CKD as well as diabetes.

Nomogram model for predicting early onset of chronic kidney disease using color Doppler region of interest technique.

The risk factors of chronic kidney disease were analyzed by using the region of interest quantitative technology of color Doppler combined with QLab software, and a Nomogram was established to conduct an individualized assessment of patients with chronic kidney disease. A total of 500 patients with chronic kidney disease diagnosed in our hospital from June 2019 to March 2021 were selected as the chronic kidney disease group, and 300 healthy patients during the same period were selected as the control group. Univariate analysis was performed on the test indexes and the vascularity index, flow index, and vascularization flow index measured by the color doppler region of interest quantitative technique. The above meaningful indicators were included in the Logistics regression analysis to obtain the independent risk factors of early chronic kidney disease. The independent risk factors were imported into R software to draw a Nomogram model for predicting early chronic kidney disease and evaluate the model. Single factor analysis results suggest age, hypertension, diabetes, hyperlipidemia, disease of heart head blood-vessel, body mass index, vascularity index, flow index, and vascularization flow index, fasting blood sugar, triglyceride, total cholesterol, urea nitrogen, creatinine, uric acid, glomerular filtration rate differences statistically significant (P < 0.05). Logistics regression analysis showed that hypertension, diabetes, flow index, and vascularization flow index, urea nitrogen, and albumin were independent risk factors for the early occurrence of chronic kidney disease. The C-index of this Nomogram using independent risk factors is 0.896 (95%CI 0.862-0.930), which indicates that the Nomogram has good discriminant power. The receiver operating curve of the histograph was area under the curve (AUC) 0.884 (95%CI 0.860-0.908). The receiver operator characteristic curve (ROC) of urea nitrogen, albumin, flow index, and vascularization flow index were evaluated. The results indicated that the best cutoff value of urea nitrogen was 5.9mmol/L, flow index was 14.67, vascularization flow index was 4.6, and albumin was 40.26g/L. In the prediction of chronic kidney disease I-II stage, the quantitative technique of color Doppler region of interest has certain diagnostic value. The model established in this study has good discriminative power and can be applied to clinical practice, giving certain indicative significance.

Chronic Kidney Disease (CKD) and Exposure to Fine Particulate Matter and Ozone: A Cross-Sectional Study Utilizing North Carolina Electronic Healthcare Records

Background and aims: Chronic kidney disease (CKD) affects more than 38 million people in the United States, predominantly those over 65 years of age. While CKD etiology is complex, recent research suggests associations with certain environmental exposures. Additional studies are needed to understand the strength of associations. We examine estimated glomerular filtration rate (eGFR) using a random sample of North Carolina electronic healthcare records (EHRs) and potential relationships with PM₂.₅ and O₃. Methods: Patient data came from a random sample of 7,065 EHRs within the EPA CARES resource, with recorded serum creatinine concentrations. Patients were seen at a University of North Carolina Healthcare System affiliated hospital or clinic from 2004-2017. We estimated eGFR using CKD-EPI equations. PM₂.₅ data comes from a hybrid model using 1x1 km grids and O₃ data from CMAQ 12x12 km grids. Exposures were annual average PM₂.₅ and O₃ based on the creatinine lab test date. We used multiple linear regression to estimate eGFR per IQR increase of PM₂.₅ &amp;#x26; O₃. We adjusted for patient sex, race, age, comorbidities, and 2010 census block group measures of sociodemographic and economic factors. Results: Patients averaged 55.3 (SD: 16.2) years of age, with 58.3% female. There were 1,001 patients (14.2%) diagnosed with CKD, identified by ICD-9 &amp;#x26; 10 codes. Mean concentrations for the study period of PM₂.₅ and O₃ were 9.92 (IQR: 1.61) µg/m³ and 40.20 (IQR: 2.53) ppb respectively. eGFR decreased 8.45 mL/min/1.73m² (95% CI: 7.92, 8.98) per IQR increase of PM₂.₅ and a more modest decrease of 0.66 mL/min/1.73m² (95% CI: -.08, 1.40) per IQR of O₃. Conclusions: Annual average PM₂.₅, and to a lesser extent O₃, were associated with lower (poorer) eGFR. Future work will examine the relationship between air pollution and onset of CKD and impaired renal function. This abstract does not reflect EPA policy.

Elevated triglycerides and reduced high-density lipoprotein cholesterol are independently associated with the onset of advanced chronic kidney disease: a cohort study of 911,360 individuals from the United Kingdom

BackgroundIncreased total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and decreased high-density lipoprotein cholesterol (HDL-C) concentrations, are established risk factors for cardiovascular morbidity and mortality; but their impact on the risk of advanced chronic kidney disease (CKD) is unclear. This study evaluates the association between the different lipid profiles and the onset of advanced CKD using a general population sample.MethodsThis observational study used records of 911,360 individuals from the English Clinical Practice Research Datalink (from 2000 to 2014), linked to coded hospital discharges and mortality registrations. Cox models were used to examine the independent association between the equal quarters of TC, TG, LDL-C, and HDL-C and the risk of advanced CKD, after adjustment for sex and age, and potential effect mediators.ResultsDuring a median follow-up of 7.5 years, 11,825 individuals developed CKD stages 4–5. After adjustment for sex and age, the hazard ratios (HRs) and confidence intervals (CIs) for CKD stages 4–5 comparing the 4th vs. 1st quarters of TG and 1st vs. 4th quarters of HDL-C were 2.69 (95% CI, 2.49–2.90) and 2.61 (95% CI, 2.42–2.80), respectively. Additional adjustment for potential effect mediators reduced the HRs to 1.28 (95% CI, 1.15–1.43), and 1.27 (95% CI, 1.14–1.41), respectively. There was no evidence of fully adjusted associations with CKD stages 4–5 for levels of either TC or LDL-C.ConclusionsElevated TG and reduced HDL-C levels are independently associated with the onset of advanced CKD. Future studies, such as in basic science and randomized trials, are needed to understand whether associations between TG and HDL-C and the development of CKD are causal.

Xenobiotics Delivered by Electronic Nicotine Delivery Systems: Potential Cellular and Molecular Mechanisms on the Pathogenesis of Chronic Kidney Disease.

Chronic kidney disease (CKD) is characterized as sustained damage to the renal parenchyma, leading to impaired renal functions and gradually progressing to end-stage renal disease (ESRD). Diabetes mellitus (DM) and arterial hypertension (AH) are underlying diseases of CKD. Genetic background, lifestyle, and xenobiotic exposures can favor CKD onset and trigger its underlying diseases. Cigarette smoking (CS) is a known modified risk factor for CKD. Compounds from tobacco combustion act through multi-mediated mechanisms that impair renal function. Electronic nicotine delivery systems (ENDS) consumption, such as e-cigarettes and heated tobacco devices, is growing worldwide. ENDS release mainly nicotine, humectants, and flavorings, which generate several byproducts when heated, including volatile organic compounds and ultrafine particles. The toxicity assessment of these products is emerging in human and experimental studies, but data are yet incipient to achieve truthful conclusions about their safety. To build up the knowledge about the effect of currently employed ENDS on the pathogenesis of CKD, cellular and molecular mechanisms of ENDS xenobiotic on DM, AH, and kidney functions were reviewed. Unraveling the toxic mechanisms of action and endpoints of ENDS exposures will contribute to the risk assessment and implementation of proper health and regulatory interventions.

Clinical significance of copeptin as an early predictor of renal graft dysfunction in renal transplant recipients

Background: Copeptin is the carboxyl-terminal part of the vasopressin precursor protein, and its concentration is an independent predictor of the onset of chronic kidney disease and a rapid decline in the glomerular filtration rate. The glomerular filtration rate is regarded as the best indicator of kidney transplant function and is a predictor of graft and patient survival. We investigated the clinical significance of copeptin as an early predictor of renal graft dysfunction in renal transplant recipients.Methods: We measured serum creatinine, cystatin C, and copeptin concentrations in renal transplant recipients on the day of their operation, as well as on postoperative days 3, 7, 30, and 365. Acute rejection was defined as a sudden decrease in renal function accompanied by histological changes.Results: Eight renal transplant recipients were enrolled in the study from July 2018 to December 2019. Four patients experienced histologically confirmed transplant rejection. All four cases involved acute T-cell rejection. No significant correlation was found between the copeptin level and the presence or absence of rejection at any time point. In subgroup analyses, changes in creatinine, the estimated glomerular filtration rate, cystatin, and copeptin did not show statistical significance.Conclusions: We anticipated that copeptin would be useful to identify individuals at high risk of transplant rejection; however, our study failed to show an association. Further research will be needed to overcome the limitations of this study.

Abstract P319: Genetic Interactions Between Novel Genes Arhgef11 And Cgnl1 Are Involved In Hypertensive Chronic Kidney Disease

Patients with hypertension are at higher risk for developing chronic kidney disease (CKD) and ultimately kidney failure. Previous genetic studies involving the Dahl salt-sensitive (SS) rat, a well-established model of hypertensive CKD, identified multiple regions linked to kidney injury. Extensive work on Chr.2 identified and characterized the role of Arhgef11 in the onset and progression of CKD using SS- Arhgef11 -/- rats. The identification of Arhgef11 and mechanism (regulation of actin cytoskeleton components) has provided an opportunity to expedite gene identification on other chromosomes based on known genetic interactions between loci, such as with Chr. 8. The effect of the Chr. 8 locus on kidney injury was previously validated using a congenic strain [S.SHR(8)]. Bioinformatics analysis of genes residing within the confidence interval, and those mechanistically linked with Arhgef11 , identified cingulin-like 1 ( Cgnl1 ) as a candidate. Cgnl1 plays a role in the regulation of cell-cell contacts via adherens and tight junctions through several interacting proteins [e.g. ZO-1 and PLEKHA7 (linked with hypertension by GWAS and an SS- Plekha7 mutant model)]. Recent studies using a novel model (SS- Cgnl1 -/- ) demonstrates that knockout of Cgnl1 leads to loss of salt-sensitive blood pressure and reduced renal injury compared to wildtype SS, supporting the congenic studies. Using multi-omics approaches incorporating bulk RNAseq, single nuclei RNAseq, spatial transcriptomics, small RNAseq, and mass spectrometry discovery proteomics, a putative mechanism connecting proximal tubule injury to alterations in sodium solute transporters and hypertension was established. The direct physiological interaction between Arhgef11 and Cgnl1 on hypertension and CKD is currently underway using a double knockout model (SS- Arhgef11 -/- Cgnl1 -/- ). In addition, to better elucidate the impact of loss of Arhgef11 , Cgnl1 , or both genes together, gene-edited cell lines using CRISPR technology has been generated and are also being studied. It is anticipated that completion of this work will lead to a better understanding of the role of genetics in hypertensive CKD, the influence of factors that complicate kidney disease, and potential new therapeutic targets.

Molecular Dynamic Simulation Reveals Structure Differences in APOL1 Variants and Implication in Pathogenesis of Chronic Kidney Disease.

Background: According to observational studies, two polymorphisms in the apolipoprotein L1 (APOL1) gene have been linked to an increased risk of chronic kidney disease (CKD) in Africans. One polymorphism involves the substitution of two amino-acid residues (S342G and I384M; known as G1), while the other involves the deletion of two amino-acid residues in a row (N388 and Y389; termed G2). Despite the strong link between APOL1 polymorphisms and kidney disease, the molecular mechanisms via which these APOL1 mutations influence the onset and progression of CKD remain unknown. Methods: To predict the active site and allosteric site on the APOL1 protein, we used the Computed Atlas of Surface Topography of Proteins (CASTp) and the Protein Allosteric Sites Server (PASSer). Using an extended molecular dynamics simulation, we investigated the characteristic structural perturbations in the 3D structures of APOL1 variants. Results: According to CASTp’s active site characterization, the topmost predicted site had a surface area of 964.892 Å2 and a pocket volume of 900.792 Å3. For the top three allosteric pockets, the allostery probability was 52.44%, 46.30%, and 38.50%, respectively. The systems reached equilibrium in about 125 ns. From 0–100 ns, there was also significant structural instability. When compared to G1 and G2, the wildtype protein (G0) had overall high stability throughout the simulation. The root-mean-square fluctuation (RMSF) of wildtype and variant protein backbone Cα fluctuations revealed that the Cα of the variants had a large structural fluctuation when compared to the wildtype. Conclusion: Using a combination of different computational techniques, we identified binding sites within the APOL1 protein that could be an attractive site for potential inhibitors of APOL1. Furthermore, the G1 and G2 mutations reduced the structural stability of APOL1.

Obesity and chronic kidney disease: A current review.

Obesity poses significant challenges to healthcare globally, particularly through its bi-directional relationship with co-morbid metabolic conditions such as type 2 diabetes and hypertension. There is also emerging evidence of an association between obesity and chronic kidney disease (CKD) which is less well characterized. A literature search of electronic libraries was conducted to identify and present a narrative review of the interplay between obesity and CKD. Obesity may predispose to CKD directly as it is linked to the histopathological finding of obesity-related glomerulopathy and indirectly through its widely recognized complications such as atherosclerosis, hypertension, and type 2 diabetes. The biochemical and endocrine products of adipose tissue contribute to pathophysiological processes such as inflammation, oxidative stress, endothelial dysfunction, and proteinuria. The prevention and management of obesity may prove critical in counteracting both the development and advancement of CKD. Moreover, measures of abdominal adiposity such as waist circumference, are generally associated with worse morbidity and mortality in individuals receiving maintenance hemodialysis. Obesity is a risk factor for the onset and progression of CKD and should be recognized as a potential target for a preventative public health approach to reduce CKD rates within the general population. Future research should focus on the use of glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors in patients with CKD and obesity due to their multi-faceted actions on major outcomes.