Biomarkers Of Kidney Injury Research Articles

Measurement of Apelin as a Biomarker and Its Relationship to Cystatin C, Copeptin, and Glomerular Filtration Rate in Serum of Patients with Acute Kidney Injury in Mosul City, Iraq

Abstract Background: There is a need for early and accurate diagnosis of acute kidney injury, as high levels of cystatin C, copeptin, and low apelin levels in serum can provide an early diagnosis of acute kidney injury in patients. Objectives: To measure the level of apelin as a biomarker in the blood serum of both control and acute kidney injury groups, and to find its relationship with each of cystatin C, copeptin, and estimated glomerular filtration rate of both groups. Materials and Methods: This study was conducted on 232 blood samples collected from males and females, 108 from control subjects and 124 from patients with acute kidney injury, aged between 35 and 56 years. Results: Serum apelin (pg/mL) levels decreased in the blood serum of the acute kidney injury patients group, increased both cystatin C and copeptin, and decreased estimated glomerular filtration rate compared to the control group. Conclusion: The results showed that serum apelin levels decreased in the blood serum of the acute kidney injury group, corresponding to an increase in the level of both cystatin C and copeptin levels and a decrease in the estimated glomerular filtration rate compared to the control group, which indicates the possibility that apelin is a strong predictive biomarker for acute kidney injury, and it can play a good preventive and therapeutic role in the future.

ASSOCIATION OF SERUM ADENOSINE DEAMINASE LEVELS WITH ACUTE KIDNEY INJURY IN DIABETIC PATIENTS

Diabetes mellitus is a significant global health issue, and complications such as acute kidney injury (AKI) are prevalent in patients with type 2 diabetes. Serum adenosine deaminase (ADA) has been suggested as a potential biomarker for various metabolic conditions, including inflammation and kidney injury, but its association with diabetic kidney health remains understudied. Objective: To assess the association of serum adenosine deaminase (ADA) levels with acute kidney injury (AKI) in patients with type 2 diabetes. Methods: This observational comparative study was conducted at DHQ Teaching Hospital KDA, Kohat, from February 7, 2023, to August 7, 2023, following ethical approval. A total of 120 participants were enrolled, including 60 patients with type 2 diabetes and 60 non-diabetic controls. Laboratory investigations for both groups included serum ADA (U/L), HbA1c (%), and estimated glomerular filtration rate (eGFR) (mL/min/1.73 m²). Statistical comparisons between groups were made using appropriate tests, and correlations between serum ADA and other parameters were assessed. Results: The mean age of diabetic patients was 55.40 ± 8.29 years, and that of controls was 54.58 ± 21.64 years. The mean serum ADA level in diabetic patients was significantly higher at 43 ± 4.29 U/L compared to 16.32 ± 1.20 U/L in controls (p = 0.0001). Diabetic patients had a mean HbA1c of 8.30 ± 0.59%, significantly higher than that of controls (5.28 ± 0.59%) (p = 0.0001). The mean eGFR in diabetic patients was 82.61 ± 17.22 mL/min/1.73 m², lower than in controls (105.97 ± 12.07 mL/min/1.73 m²) (p = 0.0001). In diabetic patients, serum ADA levels were positively correlated with HbA1c (indicating poorer glycemic control) and negatively correlated with eGFR (suggesting declining kidney function). Conclusion: Elevated serum adenosine deaminase levels in type 2 diabetic patients are significantly associated with poor glycemic control and decreased kidney function. These findings indicate that serum ADA could serve as a potential biomarker for monitoring glycemic status and kidney health in diabetic patients at risk for acute kidney injury.

Proenkephalin A 119-159 in Perioperative and Intensive Care-A Promising Biomarker or Merely Another Option?

Acute kidney injury (AKI) is a severe and prevalent syndrome, primarily observed in intensive care units (ICUs) and perioperative settings. The discovery of a new biomarker for kidney function and injury, capable of overcoming the limitations of traditional markers, has the potential to improve the diagnosis and management of AKI. Proenkephalin A 119-159 (PENK) has emerged as a novel biomarker for AKI and has been validated in various clinical settings. It has demonstrated a faster response to AKI compared to creatinine and has been shown to predict successful weaning from renal replacement therapy in the ICU. PENK has also shown promise as an AKI biomarker in perioperative patients. Additionally, PENK has been proven to be effective in estimating mortality and morbidity in patients undergoing cardiac surgery, and those with traumatic brain injury or ischemic stroke. Incorporating PENK into a novel estimation of the glomerular filtration rate, referred to as the PENK-Crea equation, has yielded promising results.

A low-dose pemetrexed-cisplatin combination regimen induces significant nephrotoxicity in mice

BackgroundPemetrexed is combined with cisplatin to treat cancer. Whether pemetrexed-cisplatin combination chemotherapy exacerbates cisplatin nephrotoxicity is unclear. Here, we investigated kidney injury in mice administered a non-lethal low-dose regimen of pemetrexed or cisplatin alone and compared it with a pemetrexed-cisplatin combination.MethodsMice were randomly divided into four groups and administered intraperitoneally the experimental drugs solubilized in captisol (sulfobutylether β-cyclodextrin). Group 1 received captisol, Group 2 pemetrexed (10 mg/kg), Group 3 cisplatin (1 mg/kg), and Group 4 pemetrexed (10 mg/kg) plus cisplatin (1 mg/kg). The mice were treated every other day for two weeks, three times per week. Glomerular filtration rate (GFR) was determined on the third day after the last treatment, followed by a necropsy.ResultsWhereas the relative kidney weight was comparable in the control vs. pemetrexed or cisplatin alone group, it was significantly increased in the combination group. Mice treated with cisplatin and pemetrexed-cisplatin combination exhibited reduced GFR. The pemetrexed-cisplatin combination caused significant increases in the plasma or urinary levels of kidney injury biomarkers, renal lipid peroxidation, and nitrosative stress compared with pemetrexed or cisplatin alone. Histopathology revealed that pemetrexed or cisplatin alone had minimal effects on the kidneys. By contrast, the pemetrexed-cisplatin combination caused tubular degeneration, dilatation, and granular casts. Live-cell imaging showed that the pemetrexed-cisplatin combination caused more severe apoptosis of primary renal epithelial cells than individual concentrations.ConclusionsThese findings suggest that combining pemetrexed and cisplatin causes oxidative kidney damage at individual doses that do not cause significant nephrotoxicity. Hence, the renal function of patients undergoing treatment with the pemetrexed-cisplatin combination needs extensive monitoring.

Fabrication of ultra-sensitive and disposable electrochemical biosensor: Detection of kidney injury molecule-1 protein in urine for diagnosis of kidney injury

This research study indicates the development of the indium tin oxide-polyethylene terephthalate (ITO-PET) coated electrode-based electrochemical biosensor system to sensitively and specifically detect kidney injury molecule-1 (KIM-1), an acute kidney injury (AKI) biomarker. The ITO-PET electrode surface was modified with 3-(Trimethoxysilyl)-1-propanethiol (3-TMESP) silane agent. Electrochemical impedance spectroscopy (EIS), cyclic voltammetry (CV), and single frequency impedance (SFI) techniques were utilized to examine the interactions between anti-KIM-1 antibody and KIM-1 antigen. The ITO-PET electrode surface was observed by scanning electron microscopy (SEM) and atomic force microscopy (AFM) to analyze the morphological characterization at each electrode development stage. Optimization studies have been conducted to determine the optimal concentrations for detecting the 3-TMESP silane agent, the NHS crosslinker, the anti-KIM-1 antibody, and the optimum incubation period for the anti-KIM-1 antibody and the KIM-1 antigen. Analytical characteristic properties of the developed biosensor, including linear determination range, and the studies of reproducibility, regeneration, repeatability, storage life, and selectivity were investigated. The KIM-1 biosensor system, based on 3-TMESP, has a broad linear range and is capable of providing sensitive measurements between 0.1 fg/mL and 1000 fg/mL. The values of low limits of detection (0.26 fg/mL) and of quantification (0.87 fg/mL) were calculated, highlighting its high sensitivity and precision in detecting KIM-1. In addition, five different commercially purchased human urine samples were tested to validate the practicability of the developed biosensor.

Heat shock protein 22 alleviates doxorubicin-induced kidney injury by suppressing oxidative stress and apoptosis

This study investigated the effects of heat shock protein 22 (HSP22) against doxorubicin (DOX)-induced kidney injury. Mice were randomly assigned to four groups: CON, ad-HSP22, DOX, and ad-HSP22 + DOX. Adeno-associated virus carrying the HSP22 gene (ad-HSP22) was administered via tail vein injection for four weeks, followed by intraperitoneal simulation with DOX (20 mg/kg) for another five days. Upon euthanasia, ELISA, histological staining (H&E, IHC, DHE, and TUNEL), and western blot analyses were employed to assess relevant markers. Serum biomarkers of kidney injury, SCr, and BUN, were upregulated after DOX administration but normalized with HSP22 overexpression. Pathological changes induced by DOX were also reversed by HSP22 overexpression in H&E, IHC, DHE, and TUNEL stains. DOX-induced upregulation of NOX-2 and NOX-4 and downregulation of SOD-1 and SOD-2 were reversed by HSP22 overexpression. Similarly, DOX-induced increases in Bax and decrease in Bcl-2 were attenuated by HSP22 overexpression. The study further demonstrated that the Nrf2/HO-1 signaling pathway was activated by HSP22 overexpression. In vitro experiments corroborated the findings from in vivo experiments. In conclusion, HSP22 alleviates DOX-induced kidney injury by suppressing oxidative stress and apoptosis, primarily through the activation of the Nrf2/HO-1 signaling pathway. These results suggest HSP22 as a potential therapeutic target for DOX-induced kidney injury.

The renal histopathology of nonproteinuric kidney impairment: a three center experience

Proteinuria is a biomarker of kidney injury that typically results from glomerular and/or tubulointerstitial disease. Whereas kidney impairment with normal urinary protein excretion is usually less focused and understudied. We conducted a retrospective review of the renal histopathology of the patients with variable degrees of unexplained renal insufficiency but with normal range proteinuria between 2014 and 2024 of three university teaching hospitals in Shenzhen city of Southern China. Patients with kidney dysfunction of undetermined or uncertain etiology and with normal urinary protein excretion (defined by a 24hr urinary protein excretion < 150 mg or spot urinary protein to creatinine ratio [PCR] < 150 mg/g) were enrolled and analyzed. In a total of 2405 patients, 53 (2.2%) fulfilled the inclusion criteria (male/female 40/13, age 47.3 ± 14.3 years) with a mean eGFR of 46.6 ± 16.8 ml/min per 1.73 m2. Glomerular disease (GD) was the most frequent pathological finding identified in 23 (43.4%) patients, while 19 (35.8%) cases showed tubulointerstitial disease (TID) and 11 (20.8%) patients exhibited small vascular disease (SVD). Patients in the TID had the lowest mean eGFR and the highest numerical 24hr urinary protein excretion among the three groups. The incidence of acute kidney injury was significantly higher in TID than in other two groups. The patients in the SVD group had the highest fraction of underlying hypertension. Kidney dysfunction with normal range proteinuria may be related with, in descending order of probablity, glomerular, tubulointerstitial and small vascular diseases. Renal biopsies were proved useful in informing therapeutic choice, long-term management and in predicting prognosis in this setting.

A-106 Determination of Urinary NGAL Reference Intervals from Specimens of Healthy Adult and Pediatric Individuals

Abstract Background Neutrophil gelatinase-associated lipocalin (NGAL) is a 25kDa protein implicated in multiple biological processes, including attenuation of apoptosis and differentiation of renal tubule epithelial cells and nephrons. NGAL is also produced and secreted by injured kidney tubule epithelial cells. As such, NGAL can serve as an early urinary biomarker for acute kidney injury (AKI). This multi-site, cross-sectional study aimed to establish reference intervals for urinary NGAL (uNGAL) in healthy pediatric and adult populations using a particle-enhanced turbidimetric assay. Methods Apparently healthy individuals, aged ≥ 3 months, were eligible for this study. Subjects with an active urinary tract infection (UTI) on the day of sample collection, acute kidney injury (AKI) or a history of AKI, stage 4 or 5 chronic kidney disease (CKD), known congenital anomalies of the kidney and urinary tract, known urothelial, urological, or kidney malignancies were excluded from the study. Subjects with uncorrected congenital heart disease, having undergone solid organ or bone marrow transplantation, receiving renal replacement therapy, and having undergone surgery (urologic, nephrectomy, or correction of congenital heart disease) were also excluded. A total of 688 subjects were screened, 677 were eligible, and 629 (91.4%) were considered evaluable per the protocol. The 59 excluded subjects were ineligible due to missing/incorrect information in the informed consent form, or not evaluable due to meeting exclusion criteria, mostly a positive UTI test. Urine samples were tested for NGAL on a Roche cobas® c501 analyzer in single determinations. Results Tables 1 and 2 describe the NGAL summary statistics and central 95% reference intervals by age and gender. Conclusions These data demonstrate the normal urine NGAL values in an apparently healthy pediatric and adult populations.

Biomarkers of acute kidney injury: a concise review of current literature

Abstract Background Acute kidney injury (AKI), a medical condition associated with increased hospitalization rates which requires interdisciplinary management, is a major health concern because of the burden it places on the health systems of different countries. Biomarkers represent the focus of recent years in furthering the early diagnosis of AKI, providing new opportunities for correct prophylaxis or early therapeutic intervention so that the evolution of patients with this pathology is favorable and the risk of life-threatening complications is negligible. Methods We performed an extensive literature search on PubMed and ScienceDirect databases, using keywords related to bio-markers for AKI. We searched for acute kidney injury (AKI), cystatin C (CYS-C), galectin-3 (GAL-3), kidney injury molecule-1 (KIM-1), neutrophil-gelatinase-associated lipocalin (NGAL), interleukin-8 (IL-8), and liver-type fatty acid-binding protein (L-FABP). We included a high number of papers, with an emphasis on more recent publications. Results Studies that analyzed the biomarkers for AKI show that CYS-C, GAL-3, KIM-1, NGAL, IL-8, calprotectin, and proteinuria were noted as potential biomarkers for early diagnosis of AKI. Conclusions Biomarkers represent the focus of recent years in furthering an early diagnosis of AKI, providing new opportunities for correct prophylaxis or early therapeutic intervention.

Tissue Inhibitor of Metalloproteinase 2 and Insulin-Like Growth Factor-Binding Protein 7 in Pediatric Diabetic Ketoacidosis

Abstract Background Diabetic ketoacidosis (DKA) is one of the main causes of end-stage kidney disease (ESKD). Urinary concentration of tissue inhibitor of metalloproteinase 2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7) are well known urinary acute kidney injury (AKI) biomarkers. Objectives to determine the level of urinary TIMP-2 and IGFBP7 as markers of acute kidney injury (AKI) in children with T1DM during and after the resolution of diabetic ketoacidosis. Patients and Methods A prospective longitudinal study was conducted over 1 year, where we have included children with T1DM presented to Emergency Department (ED) at Children’ s Hospital, Faculty of Medicine, Ain Shams University, with moderate and severe DKA, where we followed them at presentation and day 14, and determined those who developed AKI and measured urinary TIMP-2 and IGFBP7 to detect it AKI. Results We have included 40 pediatric patients with T1DM with mean (±SD) age of 10.59 ± 2.17 years, with a female predominance (90%). Among our patients, 18 patients (45%) had AKI at presentation, where they had a significantly elevated urinary level of both TIMP-2 and IGFBP7 than without AKI (TIMP-2 (ng/ml):112.58(13.76 - 190.1) versus 33.53 (17.27 - 149.65), IGFBP7(ng/ml) :77.42(0.57 - 164.3) versus 1.41(0.67 - 82.63) (p &amp;lt; 0.001). Follow up at day 14, after recovery from DKA, we had no patients with AKI, with significant decrease in the same urinary biomarkers (TIMP-2(ng/ml) :11.35 (8.13 - 25.03) versus 9.62 (7.67 - 17.02), IGFBP7(ng/ml) :0.94(0.51 - 2.34) versus 0.78 (0.43 - 1.34) (p &amp;lt; 0.005). Conclusion The level of urinary TIMP-2 and IGFBP7 increased in children and adolescent with T1DM who developed AKI at the time of presentation of DKA, and normalized after the resolution of DKA and the recovery from AKI.

Kidney and Endothelial Injury Biomarkers among Crossfit Athletes

Kidney and Endothelial Injury Biomarkers among Crossfit Athletes

Contrast-Enhanced Ultrasound (CEUS) and Ultra-Microangiography (UMA) in Critically Ill Children with Acute Kidney Injury.

Acute kidney injury (AKI) is an acute condition of impaired kidney function with decreased glomerular filtration rate, which results in dysregulation in volume, electrolyte, and acid-base equilibrium. AKI can be a life-threatening condition and can also lead to chronic kidney disease. It is important to diagnose AKI early in the course of the disease or to predict its development, as this can influence therapeutic decisions, outcome, and, consequently, the prognosis. In clinical practice, an elevated serum creatinine concentration remains the most common laboratory indicator for diagnosing AKI. However, due to the delay in its rise, creatinine levels are often insensitive and inaccurate for early diagnosis. Novel biomarkers of kidney tubular injury and the renal angina index have shown promise in predicting AKI earlier and more accurately. Contrast-enhanced ultrasonography (CEUS) and ultra-microangiography (UMA) are radiological methods that can quantify renal microperfusion and may be able to predict the development of AKI. They have not yet been used for quantifying renal perfusion in children with risk factors for developing AKI. Further research is needed to compare these sonographic techniques with the renal angina index and emerging kidney injury biomarkers for predicting acute kidney injury (AKI) in both children and adults.

Understanding Cisplatin Pharmacokinetics and Toxicodynamics to Predict and Prevent Kidney Injury.

Cisplatin is a common platinum-based chemotherapeutic that induces acute kidney injury (AKI) in about 30% of patients. Pharmacokinetic/toxicodynamic (PKTD) models of cisplatin-induced AKI have been used to understand risk factors and evaluate potential mitigation strategies. While both traditional clinical biomarkers of kidney function [e.g. serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl)] and newer subclinical biomarkers of kidney injury [e.g. urinary kidney injury molecule 1 (KIM-1), beta-2 microglobulin (B2M), neutrophil gelatinase-associated lipocalin (NGAL), calbindin, etc.] can be used to detect cisplatin-induced AKI, published PKTD models are limited to using only traditional clinical biomarkers. Previously identified risk factors for cisplatin nephrotoxicity have included dose, age, sex, race, body surface area, genetics, concomitant medications, and comorbid conditions. However, the relationships between concentrations and PK of platinum and biomarkers of kidney injury have not been well elucidated. This review discusses the evaluation of cisplatin-induced nephrotoxicity in clinical studies, mouse models, and in vitro models, and examines the available human PK and TD data. Improved understanding of the relationships between platinum PK and TD, in the presence of identified risk factors, will enable the prediction and prevention of cisplatin kidney injury. Significance Statement As cisplatin treatment continues to cause AKI in a third of patients, it is critical to improve the understanding of the relationships between platinum PK and nephrotoxicity as assessed by traditional clinical and contemporary subclinical TD markers of kidney injury. Prediction and prevention of cisplatin-induced nephrotoxicity will be advanced by the evolving development of PKTD models that incorporate kidney injury biomarkers with enhanced sensitivity and include covariates that can impact risk of developing cisplatin-induced AKI.

Comprehensive biomarker assessment for predicting severe acute kidney injury and need of kidney replacement therapy in liver transplantation patients

Background Renal dysfunction is a common complication following liver transplantation (LT). This study aimed to determine whether a comprehensive assessment of kidney function using nineteen serum and urinary biomarkers (BMs) within the first 48 h post-LT could enhance the prediction of severe acute kidney injury (AKI) and the need of kidney replacement therapy (KRT) during the first postoperative week. Methods Blood and urine (U) samples were collected during the pre- and postoperative periods. Nineteen BMs were evaluated to assess kidney health in the first 48 h after LT. Classification and regression tree (CART) cross-validation identified key predictors to determine the best BM combination for predicting outcomes. Results Among 100 LT patients, 36 developed severe AKI, and 34 required KRT within the first postoperative week. Preoperative assessment of U neutrophil gelatinase-associated lipocalin (NGAL) and liver-type fatty acid-binding protein (L-FABP) predicted the need for KRT with 75% accuracy. The combined assessment of U osmolality (OSM), U kidney injury molecule 1 (KIM-1), and tissue inhibitor of metalloproteinase (TIMP-1) within 48 h post-LT predicted severe AKI with 80% accuracy. U-OSM alone, measured within 48 h post-LT, had an accuracy of 83% for predicting KRT need, outperforming any BM combination. Conclusions Combined BM analysis can accurately predict severe AKI and KRT needs in the perioperative period of LT. U-OSM alone proved to be an effective tool for monitoring the risk of severe AKI, available in most centers. Further studies are needed to assess its impact on AKI progression postoperatively. Registered at Clinical Trials (clinicaltrials.gov) in March 24th, 2014 by title ‘Acute Kidney Injury Biomarkers: Diagnosis and Application in Pre-operative Period of Liver Transplantation (AKIB)’ and identifier NCT02095431.

From computational prediction to experimental validation: Hesperidin's anti-Urolithiatic activity in sodium oxalate-induced urolithiasis models in fruit flies and mice

Kidney stones have been a long-standing health issue, contributing to renal failure, especially in co-morbid patients. There is an increasing interest in exploring natural compounds with anti-urolithiatic properties. Our study utilized in-silico techniques followed by in vivo experiments to evaluate the anti-urolithiatic potential of selected phytoconstituents. Molecular docking studies were conducted on 11 different targets, including inhibitors of kidney stone formation, antioxidant enzymes, and biomarkers of kidney injury, to explore the potential of anti-urolithiatic effects of 38 phytoconstituents from medicinal plants possessing diuretic activity. Further, the anti-urolithiatic activity of the phytoconstituent was evaluated using a sodium oxalate-induced urolithiatic fruit fly and mouse model. Hesperidin emerged as a promising candidate, exhibiting binding interactions with a specific set of 11 target proteins involved in crystal formation with minimal free energy. Hesperidin demonstrated promising anti-urolithiatic potential in mitigating urolithiasis as evidenced by reduced crystal covered area of Malpighian tubules of fruit fly and reduced blood urea nitrogen (BUN), serum creatinine and serum sodium, potassium levels in mice. Moreover, it increased urine volume, preventing crystal deposition, and reduced urine urea nitrogen, creatinine, sodium, and potassium levels, enhancing urine flow and preventing crystal accumulation. Histopathological analysis further supported its efficacy by showing minimal crystal deposition and reduced kidney damage. Hesperidin exhibited superior effectiveness in reducing various serum and urine parameters, making it promising alternatives for urolithiasis management warranting further investigation to determine its safety and optimal dosages in human.

Evaluating nephrotoxicity reduction in a novel polymyxin B formulation: insights from a 3D kidney-on-a-chip model.

This study aimed to assess the nephrotoxicity associated with VRP-034 (novel formulation of polymyxin B [PMB]) compared to marketed PMB in a three-dimensional (3D) kidney-on-a-chip model. To model the human kidney proximal tubule for analysis, tubular structures were established using 23 triple-channel chips seeded with RPTEC/hTERT1 cells. These cells were exposed to VRP-034 or PMB at seven concentrations (1-200 µM) over 12, 24, and 48 h. A suite of novel kidney injury biomarkers, cell health, and inflammatory markers were quantitatively assessed in the effluent. Additionally, caspase and cytochrome C levels were measured, and cell viability was evaluated using calcein AM and ethidium homodimer-1 (EthD-1). Exposure to marketed PMB resulted in significantly elevated levels (P < 0.05) of four key biomarkers (KIM-1, cystatin C, clusterin, and OPN) compared to VRP-034, particularly at clinically relevant concentrations of ≥10 µM. At 25 µM, all biomarkers demonstrated a significant increase (P < 0.05) with marketed PMB exposure compared to VRP-034. Inflammatory markers (interleukin-6 and interleukin-8) increased significantly (P < 0.05) with marketed PMB at concentrations of ≥5 µM, relative to VRP-034. VRP-034 displayed superior cell health outcomes, exhibiting lower lactate dehydrogenase release, while ATP levels remained comparable. Morphological analysis revealed that marketed PMB induced more severe damage, disrupting tubular integrity. Both treatments activated cytochrome C, caspase-3, caspase-8, caspase-9, and caspase-12 in a concentration-dependent manner; however, caspase activation was significantly reduced (P < 0.05) with VRP-034. This study demonstrates that VRP-034 significantly reduces nephrotoxicity compared to marketed PMB within a 3D microphysiological system, suggesting its potential to enable the use of full therapeutic doses of PMB with an improved safety profile, addressing the need for less nephrotoxic polymyxin antibiotics.

Proteomic Correlates and Prognostic Significance of Kidney Injury in Heart Failure With Preserved Ejection Fraction.

Kidney disease is common in heart failure with preserved ejection fraction (HFpEF). However, the biologic correlates and prognostic significance of kidney injury (KI), in HFpEF, beyond the estimated glomerular filtration rate (eGFR), are unclear. Using baseline plasma samples from the TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial, we measured the following KI biomarkers: cystatin-C, fatty acid-binding protein-3, Beta-2 microglobulin, neutrophil gelatinase-associated lipocalin, and kidney-injury molecule-1. Factor analysis was used to extract the common variability underlying these biomarkers. We assessed the relationship between the KI-factor score and the risk of death or HF-related hospital admission in models adjusted for the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. We also assessed the relationship between the KI factor score and ~5000 plasma proteins, followed by pathway analysis. We validated our findings among HFpEF participants in the Penn Heart Failure Study. KI was associated with the risk of death or HF-related hospital admission independent of the Meta-Analysis Global Group in Chronic Heart Failure risk score and eGFR. Both the risk score and eGFR were no longer associated with death or HF-related hospital admission after adjusting for the KI factor score. KI was predominantly associated with proteins and biologic pathways related to complement activation, inflammation, fibrosis, and cholesterol homeostasis. KI was associated with 140 proteins, which reproduced across cohorts. Findings regarding biologic associations and the prognostic significance of KI were also reproduced in the validation cohort. KI is associated with adverse outcomes in HFpEF independent of baseline eGFR. Patients with HFpEF and KI exhibit a plasma proteomic signature indicative of complement activation, inflammation, fibrosis, and impaired cholesterol homeostasis.

Association of biomarkers of endothelial function, coagulation activation and kidney injury with persistent albuminuria in sickle cell anaemia.

Persistent albuminuria (PA) is common in sickle cell anaemia (SCA). With the association of chronic kidney disease (CKD) with increased mortality, biomarkers that predict its development or progression are needed. We evaluated the association of select biomarkers with PA in adults with SCA using Kruskal-Wallis rank-sum test and logistic regression models, with adjustment for multiple testing. Of 280 subjects, 100 (35.7%) had PA. Median plasma levels of soluble vascular cell adhesion molecule-1 (VCAM-1) (1176.3 vs. 953.4 ng/mL, false discovery rate [FDR] q-value <0.003), thrombin-antithrombin complex (5.5 vs. 4.7 ng/mL, FDR q-value = 0.04), and urinary angiotensinogen (AGT) (12.2 vs. 5.3 ng/mg, FDR q-value <0.003), urinary nephrin (30.6 vs. 27.2 ng/mg, FDR q-value = 0.04), and urinary kidney injury molecule-1 (KIM-1) (0.8 vs. 0.5 ng/mg, FDR q-value <0.003), normalized to urine creatinine, were significantly higher in subjects with PA. In multivariable analysis, only urinary AGT (odds ratio = 1.058, FDR q-value <0.0001) remained a significant predictor of PA. In addition, soluble VCAM-1 (FDR q-value <0.0001), D-dimer (FDR q-value <0.0001), urinary AGT (FDR q-value <0.0001), KIM-1 (FDR q-value <0.0001), and nephrin (FDR q-value <0.0001) were significantly associated with urine albumin-creatinine ratio in multivariable analyses. Longitudinal studies to evaluate the predictive capacity of biomarkers for the development and progression of CKD in SCA are warranted.

P091 PROENKEPHALIN CONCENTRATION AND ITS DETERMINANTS IN PATIENTS WITH END-STAGE KIDNEY DISEASE TREATED WITH HEMODIALYSIS AND PERITONEAL DIALYSIS

Background and Objective. Proenkephalin (PENK) has been recently shown to reflect glomerular dysfunction and predict new-onset acute kidney injury and heart failure. While previous studies investigated PENK utility in individuals with preserved renal function, PENK concentration in patients with end-stage kidney disease (ESKD) remained to be established. The study aimed to assess plasma PENK concentration in patients with end-stage kidney disease (ESKD) treated with hemodialysis (HD) and peritoneal dialysis (PD) and to investigate its correlation with heart failure. Additionally, we aimed to determine whether PENK is removed during a hemodialysis session. Methods. 88 patients with ESKD (41 females) undergoing HD (n=66, 75%) and PD (n=22, 25%) were enrolled in this cross-sectional study. Blood samples for PENK determination were collected before and at the end of the hemodialysis session in HD patients and at a single time point in PD patients. Plasma proenkephalin concentration was assessed using a sandwich ELISA immunoassay. Samples for measurement of creatinine, urea, and NT-proBNP were drawn simultaneously. Results. The median (IQR) plasma PENK concentration in the overall population was 1.492 ng/ml (1.071-4.380). Both median eGFR (5 mL/min/1.73 m2 [4-7] vs. 5 mL/min/1.73 m2 [4-8], p=0,856) and plasma PENK levels (1.368 ng/ml [1.068-4.030] vs. 1.706 ng/ml [1.211-5.858], p=0.305) did not differ significantly between HD and PD patients. In HD patients, median PENK concentration was significantly higher before than after hemodialysis (1.368 vs. 2.061; p=0.003). No correlation was found between PENK level and urea (p=0.192), eGFR (p=0.922), duration of dialysis (p=0.637), and residual urine output (p=0.784). Heart failure (p=0.961), EF (p=0.361), and NT-proBNP (p=0.949) were not associated with increased PENK concentration. Conclusions. Our study proved that PENK is not removed during hemodialysis session. PENK concentration does not reflect renal function and cardiac status in patients with ESKD. The fact that PENK is not removed by hemodialysis calls into question the usefulness of PENK as an everyday use biomarker in acute kidney injury.

Aminopeptidasic Enzymes as Early Biomarkers of Cardiac Surgery-Associated Acute Kidney Injury and Long-Term Events.

Diagnosis of acute kidney injury (AKI) relies on serum creatinine (SCr) changes. This study investigated if urinary aminopeptidases are early and predictive biomarkers of cardiac surgery-associated AKI (CSA-AKI). Glutamyl aminopeptidase (GluAp), alanyl aminopeptidase (AlaAp), dipeptidyl peptidase-4 (DPP4), proteinuria, albuminuria, N-acetyl-β-D-glucosaminidase (NAG), and neutrophile gelatinase-associated lipocalin (NGAL) were measured in urine samples from 44 patients at arrival in the intensive care unit (ICU) after cardiac surgery. Sensitivity, specificity, and positive and negative predictive value for diagnosis of stages 1, 2, and 3 of AKI were analyzed for the highest quartile of each marker. We also studied the relationship with SCr after surgery, 6- and 12-month glomerular filtration rates (GFRs), and other long-term events over the next 5 years. GluAp diagnosed the maximal number of patients that developed stage 2 or 3 of AKI, increasing diagnostic sensitivity from 0% to 75%. In addition, GluAp and DPP4 were related to the decrease in GFR at 6 or 12 months after surgery. Urinary aminopeptidases are a potential tool for the early diagnosis of CSA-AKI, with GluAp being the most effective marker for diagnosing stage 2 or 3 of AKI at ICU admission. GluAp and DPP4 serve as predictive biomarkers for a decrease in GFR.