Biomarkers Of Chronic Kidney Disease Research Articles

AD Biomarkers in Chronic Kidney Disease and Kidney Transplant

AbstractBackgroundBlood biomarkers of Alzheimer’s disease (AD) are elevated in chronic kidney disease (CKD). Whether this is due to deceased kidney clearance or increased production, and how they change with kidney transplant (KT), is unclear.MethodWe examined serum AD biomarkers from CKD patients pre‐ to post‐KT and compared findings with controls without CKD or AD. Analyses were performed on a Simoa HD‐X, using pTau181 and Neuro 4 Plex E assays.Age was used for covariate adjustment in linear mixed models (LMM) analyzing phosphorylated tau 181 (ptau181), neurofilament light (NfL), amyloid beta (AB42, AB40, 42/40), and glial fibrillary acidic protein (GFAP). Change in p‐tau181 was our primary outcome. LMM included age and levels for control, pre‐KT, or 12‐weeks or 1‐year post‐KT. Based on residual patterns, the natural log (In) of each measure was used for final analyses. Linear contrasts were used to generate estimated differences between group/time points from age‐adjusted models. These included averaged pre‐KT, post‐KT, and control comparisons. Two degree‐of‐freedom tests compared the post‐KT measures to pre‐KT and controls.ResultThe 59 CKD patients were 52±12 years old and 13 controls were 51±8 years old. Pre‐KT, ln(p‐tau181) was higher than controls (p<0.0001) and post‐KT (p<0.0001) (Figure). Post‐KT p‐tau181 greatly decreased but remained higher than controls (p = 0.0004). There was no difference between 12 weeks and 1 year post‐KT levels (p = 0.70). ln(pTau) increased with age (p = 0.06). ln(NfL) followed a similar pattern; pre‐KT levels were higher than controls (p<0.0001) and post‐KT (p<0.0001). Post‐KT levels decreased but remained higher than controls (p<0.0001). 12‐week and 1‐year post‐KT levels did not differ (p = 0.57). Levels increased with age (p<0.0001). Pre‐KT AB42 was higher than controls (p<0.0001) and post‐KT (p<0.0001). Post‐KT, levels decreased but remained higher than controls (p = 0.005) and continued declining 1‐year post‐transplant (p = 0.01). In(AB40) and In(GFAP) showed the same pattern. The AB42/AB40 was not different pre‐KT vs controls (p = 0.58) and did not change following KT. Cognitive function improved post‐KT. Patients with residual kidney function had lower baseline levels of AD blood biomarkers.ConclusionIn severe CKD, blood biomarkers of AD are dependent on kidney function and caution should be used in interpreting them.

Dysuricemia.

Gout results from elevated serum urate (SU) levels, or hyperuricemia, and is a globally widespread and increasingly burdensome disease. Recent studies have illuminated the pathophysiology of gout/hyperuricemia and its epidemiology, diagnosis, treatment, and complications. The genetic involvement of urate transporters and enzymes is also proven. URAT1, a molecular therapeutic target for gout/hyperuricemia, was initially derived from research into hereditary renal hypouricemia (RHUC). RHUC is often accompanied by complications such as exercise-induced acute kidney injury, which indicates the key physiological role of uric acid. Several studies have also revealed its physiological role as both an anti-oxidant and a pro-oxidant, acting as both a scavenger and a generator of reactive oxygen species (ROSs). These discoveries have prompted research interest in SU and xanthine oxidoreductase (XOR), an enzyme that produces both urate and ROSs, as status or progression biomarkers of chronic kidney disease and cardiovascular disease. The notion of "the lower, the better" is therefore incorrect; a better understanding of uric acid handling and metabolism/transport comes from an awareness that excessively high and low levels both cause problems. We summarize here the current body of evidence, demonstrate that uric acid is much more than a metabolic waste product, and finally propose the novel disease concept of "dysuricemia" on the path toward "normouricemia", or optimal SU level, to take advantage of the dual roles of uric acid. Our proposal should help to interpret the spectrum from hypouricemia to hyperuricemia/gout as a single disease category.

Development of a Genetic Risk Score for Albuminuria in Pediatric Patients with Sickle Cell Anemia

Introduction Sickle cell anemia (SCA) causes progressive, age-dependent, kidney damage. Albuminuria is an early clinical biomarker for chronic kidney disease (CKD) and is associated with progressive glomerular injury. Identifying patients at risk for albuminuria is critical for early institution of renoprotective interventions to prevent progressive kidney injury. Developing a genetic risk score (GRS) to predict albuminuria is one approach to identifying high risk patients. Our prior data demonstrates that Apolipoprotein-L1 ( APOL1 G1/G2) is associated with early development of albuminuria in children with SCA (PMID:30890594). However, this gene variant does not account for all kidney disease progression. Multiple other gene variants that modify SCA-severity have been associated with CKD in adults with SCA. We hypothesized that developing a genetic risk score (GRS) will allow for identification of pediatric patients at increased risk for development and progression of kidney disease. We aimed to develop a novel pediatric GRS that can identify pediatric SCA patients at high risk for albuminuria. Methods Gene allele variants in APOL1 G1/G2, HMOX1, BCL11A and α-thalassemia (α -3.7 allele), were identified in 324 African American patients with SCA (HbSS or HbS 0-thalassemia genotypes) enrolled in the Sickle Cell Clinical Research and Intervention Program (NCT02098863), a lifespan, longitudinal cohort study. The first urine albumin to creatinine ratio (ACR) collected after birth was analyzed as a continuous variable and dichotomized by a threshold of ACR ≥30mg/g creatinine as albuminuria. We defined a GRS 3 based on established risk alleles in three genes: APOL1 (G1/G2 ), BCL11A (rs1427407), and α -3.7(PMID:27658436). High risk was defined as patients with APOL1 (G1/G1, G2/G2 or G1/G2), without α -3.7 and with wildtype BCL11A (G/G); low-risk was defined as patients negative for APOL1 G1/G2 and with α -3.7 (either α -3.7/αα or α -3.7/α -3.7) and the BCL11A T allele (either G/T or T/T). All other combinations were defined as intermediate risk. By adding HMOX1 (rs743811), C allele (TT/TC vs CC), we further refined GRS 3 as GRS 4 using the summation of the number of high-risk alleles of kidney outcomes for four variants and created four risk categories. The generalized linear regression model was used to associate additive dose-effect models for GRS 3 and GRS 4 with continuous ACR and albuminuria, adjusted for age, sex, hydroxyurea treatment, 5 principal components, and, if significant, the age-genotype interaction. ACR was log-transformed to approximate normality. As we included variants with known associations, we used a one-sided p-value for testing associations of individual variants, GRS 3, and two-sided p-values for GRS 4. P-values <0.05 were considered significant. Results In 324 individuals with SCA, those with albuminuria (34, 10.5%) appeared to be older than those without albuminuria (290, 89.5%) (mean 9.8 years [standard deviation ±4.4 years] vs. 8.6 [± 4.0], p=0.053). There were no significant differences between these groups by sex (female 58% vs. 49%, p=0.37), proportion on hydroxyurea (62% vs. 59%, p=0.85) or fetal hemoglobin (15.6 [± 10.61] vs. 14.8% [± 10.0], p= 0.81). All four individual genetic variants were associated with the first ACR (all p ≤ 0.028) and albuminuria (all p≤ 0.03). GRS 3 was significantly associated with the first ACR (estimate=1.4, standard error [SE]=0.5, p=0.0035) and albuminuria (odds ratio [OR]=3.0, 95% CI: 1.2-7.5, p= 0.008). After adding HMOX1 to GRS 3, GRS 4 was more significantly associated with the first ACR (estimate=0.9, SE=0.3, p=0.0005) and albuminuria (OR=2.0, 95% CI: 1.2-3.4, p=0.003). Summary We developed a GRS 3 based on three genetic variants associated with albuminuria in pediatric patients with SCA and stratified patients into different risk categories. Addition of a fourth genetic variant to create GRS 4improved the model. Our findings will need to be validated in larger longitudinal studies to further examine the association between GRS 4 and development of albuminuria and chronic kidney disease. Genetic prediction strategies using GRS has the potential to identify high risk SCA patients for whom renoprotective measures could prevent the development of albuminuria.

Carbon dot-copper nanocomposite-based fluorescent sensor for detection of creatinine in urine samples of CKD patients

Creatinine (CR) is accepted as a clinical biomarker of chronic kidney disease (CKD) such as renal injury and kidney failure. To help facilitate the prognosis of CKD, a highly luminescent carbon dot (CD)-based fluorescent (FL) sensor has been built and employed for CR detection in diverse media (e.g., artificial and human urine). CDs, synthesized from sucrose precursor by a rapid microwave-assisted method (average diameter 20 nm), exhibited highly luminescent green emission upon UV exposure (λexcitation = 390 nm, λemission = 453 nm) with excellent temporal stability over three months. The nanocomposites are formed between CDs and metal ions (e.g., Cu2+) to realize the optimum biosensing of CR. Although Cu2+ ions showcases a maximum quenching (73 %) of the CDs, Cu2+/CDs system restores 77 % of the original FL intensity upon the addition of CR. The linear detection range and limit of detection for CR are estimated as 10-5 to 0.1 mg·dL-1 (R2 = 0.936) and 5.1 × 10-16 mg·dL-1, respectively. Furthermore, our biosensor shows excellent reproducibility and selectivity for CR in urine samples of healthy subjects and CKD patients. The Bland-Altman analysis for urine samples (n = 30) showcased an excellent agreement (R2 = 0.95) between our method and the gold standard ‘Jaffe’ method. These observations supported the practical utility of our method proposed for detection of CR in clinical samples.

The urinary RNA atlas of patients with chronic kidney disease

Chronic kidney disease (CKD) represents a significant global health burden. Currently employed CKD biomarkers are influenced by various factors and lack accuracy in reflecting early-stage renal fibrosis severity. Consequently, there is an urgent need for the identification of early, noninvasive CKD biomarkers. Urine, easily collectible and kidney-derived, has demonstrated potential as a diagnostic source for various kidney diseases by leveraging its RNA content. To address this, we obtained RNA-seq data pertaining to urinary RNAs from both CKD patients and healthy controls via the Gene Expression Omnibus database (GEO). The DEseq2 software was utilized to identify differentially expressed RNAs (DE-RNAs). To evaluate the overall accuracy of these DE-RNAs in urine, we performed Receiver Operating Characteristic analysis (ROC). Selected urinary RNAs were subsequently validated using reverse-transcription quantitative real-time Polymerase Chain Reaction (qRT-PCR) in conjunction with ROC analysis. Computational and experimental analyses revealed significant increases in miR-542-5p, miR-33b-5p, miR-190a-3p, miR-507, and CSAG4 within the urine of CKD patients, exhibiting high AUC values. In conclusion, our findings suggest that urinary RNAs hold promise as diagnostic biomarkers for CKD.

Prognostic Significance of Amino Acid and Biogenic Amines Profiling in Chronic Kidney Disease.

There is a pressing need for more precise biomarkers of chronic kidney disease (CKD). Plasma samples from 820 subjects [231 with CKD, 325 with end-stage kidney disease (ESKD) and 264 controls] were analyzed by liquid chromatography with tandem mass spectrometry (LC-MS/MS) to determine a metabolic profile of 28 amino acids (AAs) and biogenic amines to test their value as markers of CKD risk and progression. The kynurenine/tryptophan ratio showed the strongest correlation with estimated glomerular filtration rate values (coefficient = -0.731, p < 0.0001). Models created with orthogonal partial least squares-discriminant analysis (OPLS-DA) containing the metabolic signature showed a high goodness of fit and predictability for controls/CKD (R2X:0.73:R2Y:0.92:Q2:0.92, p < 0.0001) and lower values for CKD/ESKD (R2X:0.56:R2Y:0.59:Q2:0.55, p < 0.0001). Based on generated VIP scores, the most relevant markers for segregating samples into control/CKD and CKD/ESKD groups were citrulline (1.63) and tryptophan (1.47), respectively. ROC analysis showed that the addition of the metabolic profile to a model including CKD classic risk factors improved the AUC from 86.7% (83.6-89.9) to 100% (100-100) for CKD risk (p < 0.0001) and from 63.0% (58.2-67.8) to 96.5% (95.3-97.8) for the risk of progression from CKD to ESKD (p < 0.0001). Plasma concentrations of AAs and related amines may be useful as diagnostic biomarkers of kidney disease, both for CKD risk and for progression of CKD patients to ESKD.

Clinical Significance of Adropin and Afamin in Evaluating Renal Function and Cardiovascular Health in the Presence of CKD-MBD Biomarkers in Chronic Kidney Disease.

The study aims to test the hypothesis that concentrations of adropin and afamin differ between patients in various stages of chronic kidney disease when compared with healthy controls. The study also investigates the association of the biomarkers (adropin and afamin) with CKD-MBD and traditional cardiovascular risk parameters in CKD patients. The cross-sectional study includes the subjects divided into four groups comprising the control group (healthy volunteers = 50), CKD stages 1-2 patients (n = 50), CKD stages 3-4 patients (n = 50), CKD stage 5 patients (n = 50). Serum concentrations of adropin and afamin were determined using ELISA. Clinical variables (renal, lipid, and CKD-MBD parameters) were correlated to adropin and afamin concentrations. Afamin concentration was found to be higher in group IV, followed by groups III and II when compared to the control group, i.e., (83.243 ± 1.46, 64.233 ± 0.99, and 28.948 ± 0.72 vs. 14.476 ± 0.5) mg/L (p < 0.001), and adropin concentration was found to be lower in group IV as compared to groups III, II, and I (200.342 ± 8.37 vs. 284.682 ± 9.89 vs. 413.208 ± 12.32 vs. 706.542 ± 11.32) pg/mL (p < 0.001), respectively. Pearson correlation analysis showed that afamin was positively correlated with traditional cardiovascular risk biomarkers, while adropin showed a negative correlation. Adropin and afamin may potentially serve as futuristic predictors for the deterioration of renal function and may be involved in the pathological mechanisms of CKD and its associated complications such as CKD-MBD and high lipid levels.

Tubular toxicity of proteinuria and the progression of chronic kidney disease.

Proteinuria is a well-established biomarker of chronic kidney disease (CKD) and a risk predictor of associated disease outcomes. Proteinuria is also a driver of CKD progression toward end-stage kidney disease. Toxic effects of filtered proteins on proximal tubular epithelial cells enhance tubular atrophy and interstitial fibrosis. The extent of protein toxicity and the underlying molecular mechanisms responsible for tubular injury during proteinuria remain unclear. Nevertheless, albumin elicits its toxic effects when degraded and reabsorbed by proximal tubular epithelial cells. Overall, healthy kidneys excrete over 1000 individual proteins, which may be potentially harmful to proximal tubular epithelial cells when filtered and/or reabsorbed in excess. Proteinuria can cause kidney damage, inflammation and fibrosis by increasing reactive oxygen species, autophagy dysfunction, lysosomal membrane permeabilization, endoplasmic reticulum stress and complement activation. Here we summarize toxic proteins reported in proteinuria and the current understanding of molecular mechanisms of toxicity of proteins on proximal tubular epithelial cells leading to CKD progression.

Rational design of donor-acceptor fluorescent probe for the ratiometric point-of-care testing of human serum albumin

Human serum albumin (HSA) is an important biomarker for chronic kidney disease, cardiovascular disease, and liver disease, yet its measurement is subject to the routine clinical laboratories. Pioneering studies have demonstrated that few of the ratiometric fluorescent probes enable the point-of-care (POC) testing of HSA with the aid of affordable domestic apparatuses. Still, the lack of choices of fluorophores restricts the development of such assay. In the present work, we propose two design strategies on the typical donor-acceptor fluorescent probe via the structural engineering. The results suggest that replacement of the dimethylamino group in probe by the weaker electron donating thiophene group can effectively tune the fluorescence response to HSA from off-on to ratiometric, ideally suiting for the POC application. The screened fluorescent probe is capable of detecting HSA with the features of fast response (< 10 s), stable output, high sensitivity (limit of detection = 54 nM), tunable detection range, and great anti-interference. Moreover, the ratiometric fluorescence response to HSA can be recorded and analyzed by the portable miniaturized paper-based or 3D-printed devices at the point of need. The success of structural engineering in the present study provides an efficient way to rationally regulate the fluorescence response mode of the donor-acceptor probes.

Symmetric Dimethylarginine as a Biomarker for Chronic Kidney Disease

Symmetric dimethylarginine (SDMA), is a post-translationally stable catabolic product of arginine-methylated proteins that plays an important role in basic cellular metabolism. SDMA is an endogenous biomarker of kidney function that has been widely used in veterinary medicine. Symmetric dimethylarginine (SDMA) and asymmetric dimethylarginine (ADMA) are 2 constant products of L-arginine proteolysis that undergo methylation. SDMA is almost completely excreted by the kidneys after filtration making SDMA an ideal GFR biomarker candidate. Apart from that, SDMA has several advantages as a biomarker of kidney function, namely that it is not affected by non-renal factors that influence creatinine and cystatin C. Apart from that, SDMA also increases earlier than other biomarkers.

Alternation in the Abundance and Phosphorylation Status of Aquaporin-2 in the Serum Exosome of Patients with Chronic Kidney Disease

Background: Exosomes, which are vesicles ranging from 40 to 160 nm in size, are released from cellular membranes and serve as a means of cell-to-cell communication by delivering their contents, such as microRNA and protein, to recipient cells. These extracellular vesicles are present in human blood and urine and their composition can be altered in specific pathogenic conditions. Aquaporin-2 (AQP2) is a critical aquaporin involved in water homeostasis and has been identified as an important biomarker in chronic kidney disease. However, it is unclear whether AQP2 is transported via exosomes. Method: This study included 16 participants with chronic kidney disease and 11 healthy volunteers. Serum exosomes were isolated through polymer precipitation and imaged using transmission electron microscopy. The diameter of purified serum exosomes was measured via flow cytometry, and their identity was further confirmed by identifying exosome markers through immunoblotting. Additionally, the participants’ hepatic B and C virus infection status was determined using chemiluminescent microparticle immunoassay. Results: The precipitation method was utilized to isolate serum exosomes, and successful purification was confirmed through transmission electron microscopy imaging. Size estimation was conducted via flow cytometry, and the presence of exosome markers CD63, TSG101, CD9, and CD81 was confirmed through immunoblotting. Furthermore, the presence of AQP2 was detected in serum exosomes, and its abundance was found to significantly decrease in patients with chronic kidney disease. However, despite the decreased abundance, the percentage of phosphorylated AQP2 at serine 256 was significantly increased. Conclusion: Our findings suggest that changes in the abundance and phosphorylation status of AQP2 on serum exosomes are associated with the development of chronic kidney disease, and could potentially serve as a signal for exosome transport.

Cell-free DNA as a plausible biomarker of chronic kidney disease.

Circulating cell-free DNA (cf-DNA) is released from dead and/or apoptotic leukocytes and due to neutrophil extracellular traps contributing to an inflammatory response. Previous clinical studies have reported that the peak concentrations and dynamic changes of cf-DNA may be used asanoninvasive biomarker of worsening kidney function as well asa guide to themanagement of kidney allograft rejection. We hypothesized that the pattern and dynamic changes of cf-DNA might be aplausible predictive biomarker for patients at risk of chronic kidney disease (CKD), including individuals with type 2 diabetes mellitus, heart failure, cardiovascular diseaseand established CKD. Along with it, pre- and posthemodialysis levels of serum cf-DNA appearto be aindependent predictor for all-cause mortality in patients with end-stage kidney disease.

Serum miRNA-146a and vitamin D values in chronic renal ailment with and without comorbid cardiovascular disease

ABSTRACT Chronic kidney disease (CKD) is a global concern and is a serious health issue that is closely associated with cardiovascular disease (CVD). Accordingly, there is a rising clinical demand for promoting the importance of the screening and diagnosis of CVD in CKD patients. The purpose of this research was to assess the effectiveness of blood microRNA-146a and vitamin D levels in CKD detection and cardiovascular complications prediction. When CKD participants, either complicated or not, were compared to the control group, plasma rates of Vascular adhesion molecule-1 (VCAM-1) and microRNA-146a were greater, while serum vitamin D values were markedly smaller. Hence, although blood miR-RNA146a quantities can be used as a reliable and particular CKD biomarker, they cannot be used to identify CVD in CKD patients since its level was not significantly different in CKD and CKD+CVD patients.

Nicotinamide N-Methyl Transferase as a Predictive Marker of Tubular Fibrosis in CKD.

Chronic kidney disease (CKD) progression is complex. There are not standardized methods for predicting the prognosis of CKD. Nicotinamide N-methyltransferase (NNMT) has been shown to be associated with renal fibrosis. This study aimed to validate NNMT as a prognostic biomarker of progressive CKD. We explored the relationship between NNMT expression and CKD-related outcome variables using the NephroseqV5 and GEO databases. Additionally, a validation set of 37 CKD patients was enrolled to measure the correlation between NNMT expression levels and CKD outcomes. Furthermore, single-cell RNA sequencing data and the Human Protein Atlas were reanalyzed to investigate the expression specificity of NNMT in the kidney. Finally, to detect the status of NNMT expression with tubular fibrosis in vivo, we constructed a unilateral ureteral obstruction (UUO) mouse treated with an NNMT inhibitor. Analyzing the datasets showed that NNMT was expressed mainly in proximal tubule compartments. And patients with high NNMT expression levels had a significantly lower overall survival rate compared to those with low NNMT expression levels (P = 0.013). NNMT was independent of prognosis factors in the multivariate Cox regression model, and the AUCs for CKD progression at 1, 3, and 5 years were 0.849, 0.775, and 0.877, respectively. Pathway enrichment analysis indicated that NNMT regulates the biological processes of tubulointerstitial fibrosis (TIF). In the validation group, NNMT levels were significantly higher in the CKD group combined with interstitial fibrosis. In vivo, NNMT was a high expression in the UUO group, peaking at postoperative day 21. Treatment with an NNMT inhibitor improved renal tubular interstitial fibrosis, and expression levels of FN, α-SMA, VIM, and TGF-β1 were decreased compared with UUO (P < 0.05). NNMT was expressed mainly in tubular renal compartments, and associated with CKD prognosis. It holds potential as a diagnostic biomarker for tubular fibrosis in CKD.

Exploration of Potential Breath Biomarkers of Chronic Kidney Disease through Thermal Desorption-Gas Chromatography/Mass Spectrometry.

Breath volatile organic compound (VOC) analysis is a non-invasive tool for assessing health status; the compositional profile of these compounds in the breath of patients with chronic kidney disease is believed to change with decreasing renal function. We aimed to identify breath VOCs for recognizing patients with chronic kidney disease. Using thermal desorption-gas chromatography/mass spectrometry, untargeted analysis of breath markers was performed using breath samples of healthy controls (n = 18) versus non-dialysis (n = 21) and hemodialysis (n = 12) patients with chronic kidney disease in this cross-sectional study. A total of 303 VOCs alongside 12 clinical variables were used to determine the breath VOC profile. Metabolomic analysis revealed that age, systolic blood pressure, and fifty-eight breath VOCs differed significantly between the chronic kidney disease group (non-dialysis + hemodialysis) and healthy controls. Thirty-six VOCs and two clinical variables that showed significant associations with chronic kidney disease in the univariate analysis were further analyzed. Different spectra of breath volatile organic compounds between the control and chronic kidney disease groups were obtained. A multivariate model incorporating age, 2-methyl-pentane, and cyclohexanone showed high performance (accuracy, 86%) in identifying patients with chronic kidney disease with odds ratios of 0.18 (95% CI, 0.07-2.49, p = 0.013); 2.10 (0.94-2.24, p = 0.025); and 2.31 (0.88-2.64, p = 0.008), respectively. Hence, this study showed that renal dysfunction induces a characteristic profile of breath VOCs that can be used as non-invasive potential biomarkers in screening tests for CKD.

Comprehensive analysis of the relationship between xanthine oxidoreductase activity and chronic kidney disease

Chronic kidney disease (CKD) is a common disease that seriously endangers human health. However, the potential relationship between xanthine oxidoreductase (XOR) activity and CKD remains unclear. In this study, we used clinical data, CKD datasets from the Gene Expression Omnibus database, and untargeted metabolomics to explain the relationship between XOR activity and CKD. First, XOR activity showed high correlation with the biomarkers of CKD, such as serum creatinine, blood urea nitrogen, uric acid, and estimated glomerular filtration rate. Then, we used least absolute shrinkage and selection operator logical regression algorithm and random forest algorithm to screen CKD molecular markers from differentially expressed genes, and the results of qRT-PCR of XDH, KOX-1, and ROMO1 were in accordance with the results of bioinformatics analyses. In addition, untargeted metabolomics analysis revealed that the purine metabolism pathway was significantly enriched in CKD patients in the simulated models of kidney fibrosis.

Renal injury, biomarkers, and myositis, an understudied aspect of disease: prospective study in the MyoCite cohort.

The mechanisms leading to chronic kidney disease (CKD) in patients with idiopathic inflammatory myopathies (IIMs) are poorly understood. We assessed the prevalence of subclinical renal injury in patients with IIMs, through elevation in biomarker levels of tubular injury and fibrosis (NGAL, KIM1, Activin A, CD163, and Cys-c), and assessed differences between subtypes of IIMs, and the effect of disease activity and duration. Clinical data, core set measures, sera and urine were prospectively collected from all patients enrolled in the MyoCite cohort from 2017 to 2021. Twenty healthy subjects (HC) and 16 patients with acute kidney injury (AKI) were included as controls. Baseline and follow up data for IIMs were included. Enzyme-linked immunosorbent assay (ELISA) was used to measure urine NGAL (Human Lipocalin-2/NGAL Duoset ELISA, Cat no: DY1757), KIM1 (Human TIM-1/KIM 1/HAVCR Duoset ELISA, Cat.no: DY1750B), Activin A (Human Activin A Duoset ELISA, Cat no: DY338), CD163 (Human CD163 Duoset ELISA,Cat no: DY1607-05), and Cys-c (Human Cystatin C Duoset ELISA, Cat. no.: DY1196) levels, while eGFR (unit mL/min/1.73 m2) was calculated by the Cockcroft-Gault formula and CKD-EPI formula. Analysis of 201 visits of 110 adult patients with IIMs indicated higher normalized biomarker levels compared to HCs, and comparable to patients with AKI, with the exception of NGAL, which was higher in the AKI group. Notably 72 (49%) patients with IIMs had eGFR<90; the levels of the 5 biomarkers were comparable between active and inactive IIMs, and different subtypes of IIMs. Similarly, a poor correlation between urine biomarker levels and core set measures of activity and damage was found. Changes in biomarker levels on follow-up did not correlate with eGFR changes. This exploratory analysis of urinary biomarkers identified low eGFR and elevated biomarkers of CKD in nearly half of the patients with IIMs, comparable to patients with AKI and higher than HCs, indicative of potential renal damage in IIMs that may have a lead to complications in other systems.

423-P: Urinary Extracellular Vesicles in African Americans with Chronic Kidney Disease With and Without Type 2 Diabetes Mellitus

Introduction: Type 2 diabetes (T2D) is the leading cause for chronic kidney disease (CKD). Novel biomarkers are critical in early detection of CKD. Methods: Healthy Eatonville Project (HEP) was a prospective study (n=300, females (F)=71%, T2D 32%, CKD 25%) in historically black community of Eatonville, FL. We characterized EVtrap®-isolated urinary extracellular vesicles (uEV) proteins from a balanced HEP cohort of 48 African Americans (mean age 62y, F=73%, BMI 32.2 kg/m2, T2D 46%) with CKD risk ranging from low, intermediate, to high-very high (H-VH), with and without T2D. Differential expression and coexpression network analyses were implemented. Results: We detected 5265 uEV proteins, 46 of which were significantly (fold change&amp;gt;1.5, P&amp;lt;0.05, FDR&amp;lt;0.1) differentially expressed (DE) in CKD risk groups. Of those, 24 were significantly upregulated in H-VH risk CKD (Figure Module Pr.1). A set of 15 DE proteins appeared to represent a protective pathway against CKD (Figure Module Pr.2). Key biomarkers of acute kidney injury IGFBP7, TIMP2, and IL18 had significant negative correlations with CKD risk (-0.59 ≤ r ≤ -0.44, P&amp;lt;0.002). Supporting our findings, several of these biomarkers had been previously reported in kidney disease studies. Conclusion: The uEV proteomic landscape is representative of kidney pathophysiology and suggests potential biomarkers of CKD in Africans Americans. Disclosure T.K.Thethi: Other Relationship; Bayer Inc., Novo Nordisk. A.Bilal: None. M.S.Zaino: None. A.Iliuk: None. R.E.Pratley: Other Relationship; Bayer Inc., Corcept Therapeutics, Dexcom, Inc., Gasherbrum Bio, Inc., Hanmi Pharm. Co., Ltd., Hengrui (USA) Ltd., Merck Sharp &amp; Dohme Corp., Novo Nordisk, Pfizer Inc., Rivus Pharmaceuticals Inc., Sanofi, Scohia Pharma Inc., Sun Pharmaceutical Industries Ltd. Y.O.Nunez lopez: None.

#5590 PRE-DIALYSIS TRAJECTORIES OF ESTIMATED GFR AND CONCURRENT TRENDS OF CKD-RELEVANT BIOMARKERS

Abstract Background and Aims The glomerular filtration rate (GFR) decline varies in patients with advanced chronic kidney disease (CKD), and the concurrent changes in CKD-related biomarkers are unclear. Method We adopted a group-based trajectory model to categorize CKD patients by their pre-dialysis eGFR trajectory and then analyzed the concurrent changing trends of CKD-relevant biomarkers, including urine protein-creatinine ratio (UPCR), albumin, and uric acid. Results Using longitudinal data from two years before dialysis initiation, 1,758 CKD patients were included. We identified three distinct eGFR trajectories: persistently low eGFR levels, progressive loss of eGFR, and accelerated loss of eGFR. Eight of the 15 biomarkers showed distinct patterns among the trajectory groups. Compared to the group with persistently low eGFR values, the other two groups were associated with a more rapid increase in the serum urea level and UPCR, especially in the year before dialysis initiation, and a more rapid decline in hemoglobin and platelet counts. Rapid eGFR decline was associated with lower levels of albumin and potassium, and higher levels of MCHC and WBC. The albumin level in the group with an accelerated loss of eGFR was below the normal range. Overall, there was a total of 691 (39.3%) deaths observed during the follow-up period. In the 2-year and 5-year follow-up, 302 (17.2%) and 549 (31.2%) deaths were observed, respectively. The corresponding median follow-up times were 2 years (IQR:1.6 – 2.0) and 3.3 years (IQR:1.6 –5.0). Kaplan–Meier survival plots showed that the eGFR trajectory was significantly associated with the risk of mortality two years and five years after dialysis, with the log-rank test P = .0057 and P = .0001, respectively Conclusion The changes in CKD biomarkers were delineated with disease progression. The results provide information to clinicians and clues to elucidate the mechanism of CKD progression.

#3115 THE ASSOCIATION OF FIBROBLAST GROWTH FACTOR-23 AND CARDIORENAL SYNDROME IN PATIENTS WITH DIABETES MELLITUS

Abstract Background and Aims Previous studies suggest that interactions between the heart and the kidney can contribute to the progressive dysfunction of both organs. Recently, there has been an increase in the prevalence of cardiovascular disease (CVD) and chronic kidney disease (CKD) due to increasing diabetes mellitus rate. It is known that fibroblast growth factor-23 (FGF-23) has been found to be related to kidney metabolism especially as a biomarker and a key factor to be used in the kidney field. The aim of our study was to assess potential therapeutic approaches of the use of FGF-23 in clinical settings as a potential circulating biomarker for CVD and CKD. Method A total of 155 patients with DT2, aged 34 to 84 years (60 [60;72]), were examined. Control group included 94 healthy people the same age. All patients underwent standard clinical and laboratory examination, with an assessment of the levels of FGF-23 in baseline plasma samples. Renal function was assessed based on the levels of serum creatinine, cystatin C, eGFR, which was calculated according to the CKD-EPI formula, and albuminuria, which was assessed as albumin/creatinine ratio (A/C). An echocardiographic examination was conducted according to the standard protocol with the calculation of dimensional, volume and speed characteristics. Results The levels of FGF-23 were significantly higher in DT2 patients with CKD 5 in comparison with stages 1–4. There were positive strong significant association between FGF-23 and creatinine (r = 0.71, p&amp;lt;0.001). In both unadjusted and adjusted analyses, probability of decreased eGFR was associated strongly with FGF-23 (COR; 95% CI 1.890; 1.362-2.622, p&amp;lt;0,001). When evaluating the dependence of the probability of decreased eGFR on the FGF-23 using the ROC analysis, the cut-off value of FGF-23 was 0,9 pmol/l. The sensitivity and specificity of the method were 75.3% and 74.5%, respectively (AUC 0.832±0.035 with 95% CI: 0.764-0.901, p&amp;lt;0.001). DT2 patients with left ventricular hypertrophy (LVH) were characterized by higher levels of FGF-23 (2,45 [0,65;7,43] vs 0,57 [0,19;2,19] pmol/l in control group). DT2 patients with LVH and natriuretic peptides levels ≥ 35 pg/ml for BNP and/or ≥125 ng/ml for NT-proBNP had significantly high concentrations of FGF-23 than patients with normal levels of natriuretic peptides (3,22 [1,09;9,55] vs. 0,52 [0,27;1,08] pmol/l, p&amp;lt;0,0001). In order to assess the diagnostic significance of the FGF-23 for predicting left ventricular mass index (LVMI) thickening and increasing the proBNP concentration, a ROC analysis was performed. Thus, at the level of FGF-23 (AUC-0.702) = 0.9 pmol/l, the sensitivity and specificity for LVMI thickening were 66.9% and 67.3%. Conclusion Our study identifies FGF-23 as a promising target of novel therapeutic interventions in cardiorenal syndrome, which should be investigated in future clinical studies.