Biomarkers Of Kidney Injury Research Articles

Simultaneous determination of multiple urine biomarkers for kidney injury using SPE combined with LC-MS/MS

Background and ObjectivesUrinary biomarkers such as low molecular weight proteins and small molecular weight metabolites are crucial in the diagnosis of kidney injury. The objective of this study was to develop and preliminarily validate a sensitive and specific method using solid-phase extraction (SPE) in conjunction with liquid chromatography–tandem mass spectrometry (LC-MS/MS) for the simultaneous measurement of these biomarkers in human urine. MethodThis study presents the development of a solid-phase extraction method integrated with LC-MS/MS analyzing biomarkers including creatinine, urea, β2-microglobulin, α1-microglobulin, and cystatin C in human urine. An enhanced solid-phase cartridge technique was employed for peptide purification and dilution of small molecule metabolites during sample preparation. ResultsThe developed LC-MS/MS method achieved satisfactory separation of the five analytes within 15 min. Accuracy levels ranged from −8.6% to 13.6%. Both intra-assay and inter-assay imprecision rates were maintained below 7.9% for all analytes. ConclusionsThe established LC-MS/MS method effectively quantifies creatinine, urea, β2-microglobulin, α1-microglobulin and cystatin C concurrently. This offers a viable alternative for the detection of kidney injury biomarkers in human urine, demonstrating potential for clinical application in kidney injury diagnosis.

Impact of low pneumoperitoneum on renal function and acute kidney injury biomarkers during robot-assisted radical prostatectomy (RARP): a randomised clinical trial

The objective of this study was to evaluate the effect of low pneumoperitoneum pressure (Pnp) on renal function and renal injury biomarkers during robot-assisted radical prostatectomy (RARP). A single-centre, triple-blinded, randomised clinical trial was conducted with 98 patients undergoing RARP, who were assigned to either standard Pnp of 12 mmHg or low Pnp of 7 mmHg. The primary outcome was urinary neutrophil gelatinase-associated lipocalin (u-NGAL), and several other kidney injury biomarkers were assessed as secondary outcomes. Acute kidney injury (AKI) was evaluated using the Kidney Disease Improving Global Outcomes (KDIGO) criteria, the gold standard method for defining AKI. The trial was registered on ClinicalTrials.gov (NCT04755452). Patients in the low Pnp group had significantly lower levels of u-NGAL (mean difference − 39.9, 95% CI − 73.7 to − 6.1, p = 0.02) compared to the standard Pnp group. No significant differences were observed for other urinary biomarkers. Interestingly, there was a significant difference in intraoperative urine production between the groups (low Pnp median: 200 mL, IQR: 100–325 vs. standard Pnp median: 100 mL, IQR: 50–200, p = 0.01). Similarly, total postoperative urine production also varied significantly (low Pnp median: 1325 mL, IQR: 1025–1800 vs. standard Pnp median: 1000 mL, IQR: 850–1287, p = 0.001). The occurrence of AKI, as defined by the KDIGO criteria, did not differ significantly between the groups. Low Pnp during RARP resulted in lower u-NGAL levels, suggesting a potential benefit in terms of reduced renal injury. However, the lack of a notable difference in AKI as defined by the KDIGO criteria indicates that the clinical significance of this finding may be limited. Further research is needed to validate and expand on these results, ultimately defining the optimal Pnp strategy for RARP and improving patient outcomes.

Toward Precision Medicine: Exploring the Landscape of Biomarkers in Acute Kidney Injury.

Acute kidney injury (AKI) remains a complex challenge with diverse underlying pathological mechanisms and etiologies. Current detection methods predominantly rely on serum creatinine, which exhibits substantial limitations in specificity and poses the issue of late-stage detection of kidney injury. In this review, we propose an up-to-date and comprehensive summary of advancements that identified novel biomarker candidates in blood and urine and ideal criteria for AKI biomarkers such as renal injury specificity, mechanistic insight, prognostic capacity, and affordability. Recently identified biomarkers not only indicate injury location but also offer valuable insights into a range of pathological processes, encompassing reduced glomerular filtration rate, tubular function, inflammation, and adaptive response to injury. The clinical applications of AKI biomarkers are becoming extensive and serving as relevant tools in distinguishing acute tubular necrosis from other acute renal conditions. Also, these biomarkers can offer significant insights into the risk of progression to chronic kidney disease CKD and in the context of kidney transplantation. Integration of these biomarkers into clinical practice has the potential to improve early diagnosis of AKI and revolutionize the design of clinical trials, offering valuable endpoints for therapeutic interventions and enhancing patient care and outcomes.

Effects of high-intensity intermittent exercise versus moderate-intensity continuous exercise on renal hemodynamics assessed by ultrasound echo.

High-intensity intermittent exercise (HIIE) has become attractive for presenting a variety of exercise conditions. However, the effects of HIIE on renal function and hemodynamics remain unclear. This study aimed to compare the effects of HIIE and moderate-intensity continuous exercise (MICE) on renal hemodynamics, renal function, and kidney injury biomarkers. Ten adult males participated in this study. We allowed the participants to perform HIIE or MICE to consider the impact of exercise on renal hemodynamics under both conditions. Renal hemodynamic assessment and blood sampling were conducted before the exercise (pre) and immediately (post 0), 30 min (post 30), and 60 min (post 60) after the exercise. Urine sampling was conducted in the pre, post 0, and post 60 phases. There was no condition-by-time interaction (p = 0.614), condition (p = 0.422), or time effect (p = 0.114) regarding renal blood flow. Creatinine-corrected urinary neutrophil gelatinase-associated lipocalin concentrations increased at post 60 (p = 0.017), but none exceeded the cut-off values for defining kidney injury. Moreover, there were no significant changes in other kidney injury biomarkers at any point. These findings suggest that high-intensity exercise can be performed without decreased RBF or increased kidney injury risk when conducted intermittently for short periods.

Urinary SIRT2 Reflects Kidney Injury in Type 2 Diabetes

Introduction: The early diagnosis of kidney injury in type 2 diabetes (T2DM) is important to prevent the long-term damaging effects of kidney loss and is decisive for patient outcomes. While SIRT2 is implicated in diabetes pathogenesis, its correlation with diabetic nephropathy remains unexplored. This study was designed to evaluate the association of urine SIRT2 levels with diabetic kidney injury, as well as potential underlying mechanisms. Methods: In T2DM patients, db/db mice, and high glucose plus palmitic acid treated HK2 cell models, ELISA, Immunoturbidimetry, Immunohistochemistry, Western blot, and Quantitative real-time polymerase chain reaction were used to detect SIRT2 levels and kidney damage. According to urinary albumin/creatinine ratio (UACR), 163 T2DM patients were divided into three groups. Spearman correlation analysis was used to investigate the relationship between urinary sirtuin2/creatinine ratio (USCR) and biomarkers of kidney injury. The influencing factors of albuminuria in T2DM patients were analyzed by logistic regression model. Results: In our findings, the Macro group exhibited the highest USCR levels as UACR increased. There was a positive association between USCR and UACR, α1-microglobulin/creatinine ratio (UαCR), β2-microglobulin/creatinine ratio (UβCR), and retinol-binding protein/creatinine ratio (URCR), with a negative correlation observed with eGFR. Logistic ordered multiclassification regression analysis, adjusting for confounding variables, confirmed that USCR remained a significant risk factor for the severity of albuminuria in T2DM patients. In the db/db mice kidney SIRT2 protein level increased significantly. Increased SIRT2 protein levels were also observed in renal tubular epithelial cells treated with high glucose plus palmitic acid. Moreover, SIRT2 promotes the expression of proinflammatory factors TNF-α and IL-6 by modulating the phosphorylation of p38 MAPK and p-JNK in renal tubular cells induced by high glucose and palmitic acid. Conclusion: Urinary SIRT2 is closely related to eGFR, renal tubule injury, and urinary albumin excretion in T2DM patients, which is expected to be an important indicator to comprehensively reflect renal injury.

Review of the limitations of current biomarkers in acute kidney injury clinical practices.

Acute kidney injury is a prevalent disease in hospitalized patients and is continuously increasing worldwide. Various efforts have been made to define and classify acute kidney injury to understand the progression of this disease. Furthermore, deviations from structure and kidney function and the current diagnostic guidelines are not adequately placed due to baseline serum creatinine values, which are rarely known and estimated based on glomerular function rate, resulting in misclassification of acute kidney injury staging. Hence, the current guidelines are still developing to improve and understand the clinical implications of risk factors and earlier predictive biomarkers of acute kidney injury. Yet, studies have indicated disadvantages and limitations with the current acute kidney injury biomarkers, including lack of sensitivity and specificity. Therefore, the present narrative review brings together the most current evidenced-based practice and literature associated with the limitations of the gold standard for acute kidney injury diagnoses, the need for novel acute kidney injury biomarkers, and the process for biomarkers to be qualified for diagnostic use under the following sections and themes. The introduction section situates the anatomy and normal and abnormal kidney functions related to acute kidney injury disorders. Guidelines in providing acute kidney injury definitions and classification are then considered, followed by a discussion of the disadvantages of standard markers used to diagnose acute kidney injury. Characteristics of an ideal acute kidney injury biomarker are discussed concerning sensitivity, specificity, and anatomic location of injury. A particular focus on the role and function of emerging biomarkers is discussed in relation to their applications and significance to the prognosis and severity of acute kidney injury. Findings show emerging markers are early indicators of acute kidney injury prediction in different clinical settings. Finally, the process required for a biomarker to be applied for diagnostic use is explained.

Robust Rat and Mouse Models of Bilateral Renal Ischemia Reperfusion Injury.

Acute and chronic kidney diseases are a major contributor to morbidity and mortality worldwide, with no specific treatments currently available for these. To enable understanding the pathophysiology of and testing novel treatments for acute and chronic kidney disease, a suitable in vivo model of kidney disease is essential. In this article, we describe two reliable rodent models (rats and mice) of efficacious kidney injury displaying acute to chronic kidney injury progression, which is also reversible through novel therapeutic strategies such as ischemic preconditioning (IPC). We utilized adult male Lewis rats and adult male wildtype (C57BL/6) mice, performed a midline laparotomy, and induced warm ischemia to both kidneys by bilateral clamping of both renal vascular pedicles for a set time, to mimic the hypoxic etiology of disease commonly found in kidney injury. Bilateral ischemia reperfusion injury caused marked structural and functional kidney injury as exemplified by histology damage scores, serum creatinine levels, and kidney injury biomarker levels in both rodents. Furthermore, this effect displayed a dose-dependent response in the mouse model. These rodent models of bilateral kidney IRI are reliable, reproducible, and enable detailed mechanistic study of the underlying pathophysiology of both acute and chronic kidney disease. They have been carefully optimised for single operator use with a strong track record of training both surgically trained and surgically naïve operators.

Immunoaffinity proteomics for kidney injury biomarkers in male beagle dogs.

Drug-induced kidney injury (DIKI) is a cause of drug development failure. Dogs represent a common non-rodent animal model in pre-clinical safety studies; however, biomarker assays for detecting nephrotoxicity in dogs are limited. To identify novel proteins and gain insight into the molecular mechanisms involved in DIKI, we developed an assay to evaluate proteomic changes associated with DIKI in male beagle dogs that received nephrotoxic doses of tobramycin for 10 consecutive days. Label-free quantitative discovery proteomics analysis on representative kidney cortex tissues collected on Day 11 showed that the tobramycin-induced kidney injury led to a significant differential regulation of 94 proteins mostly associated with mechanisms of nephrotoxicity such as oxidative stress and proteasome degradation. For verification of the proteomic results, we developed a multiplex peptide-centric immunoaffinity liquid chromatography tandem mass spectrometry assay (IA LC-MS/MS) to evaluate the association of eight DIKI protein biomarker candidates using kidney cortices collected on Day 11 and urine samples collected on Days -4, 1, 3, 7 and 10. The results showed that most biomarkers evaluated were detected in the kidney cortices and their expression profile in tissue aligned with the label-free data. Cystatin C was the most consistent marker regardless of the magnitude of the renal injury while fatty acid-binding protein-4 (FABP4) and kidney injury molecule-1 (KIM-1) were the most affected biomarkers in response to moderate proximal tubular injury in absence of changes in serum-based concentrations of blood urea nitrogen or creatinine. In the urine, clusterin is considered the most consistent biomarker regardless of the magnitude and time of the renal injury. To our knowledge, this is the most comprehensive multiplex assay for the quantitative analysis of mechanism-based proximal tubular injury biomarkers in dogs.

EVALUATION OF PHYSIOLOGICAL BIOMARKERS AS POSSIBLE PREDICTIVE FACTORS AND PROGNOSIS MARKERS OF KIDNEY INJURY IN DOGS NATURALLY INFECTED WITH LEISHMANIA INFANTUM

Impaired renal function is one of the main characteristics of dogs infected with Leishmania infantum. Early diagnosis of kidney injury is essential for improving patient’s prognosis. This study aims to evaluate physiological biomarkers as predictors of kidney injury and prognostic markers. Medical records of fifty-nine dogs of different breed, age, and sex, naturally infected with L. infantum, were analyzed. Red blood cells, leucocytes, platelets count, hematocrit, total plasma proteins, plasma globulin, plasma albumin, serum creatinine, serum urea, serum phosphorus, serum symmetrical dimethyl arginine, urine analysis, urinary density, urinary protein creatinine ratio, urinary creatinine, urinary protein, and systemic blood pressure were examined in trial 0. Six months after trial 0, twenty-four dogs returned for clinical and laboratory examination. The second medical record analysis was identified as trial 1. The twenty-four dogs were examined using the same tests performed in trial 0. The physiological biomarker such as platelets and leukocyte count, hematocrit, serum phosphorus, urinary density, and systemic blood pressure, showed a significant correlation as prognostic and predictive factors of kidney injury in dogs. The platelet count was used as the physiological biomarker to show the value as a predictive factor and prognostic marker related to biomarkers of kidney injury in dogs naturally infected with L. infantum.

Assessment of the dynamics of concentration of biomarkers of acute kidney injury in remote shock wave lithotripsy in children

BACKGROUND: For several decades, remote shock wave lithotripsy has been considered a universally recognized gold standard for the treatment of upper urinary tract concrements. Despite its noninvasiveness, each lithotripsy session causes acute kidney injury which cannot be reliably assessed with traditional indicators used in nephrourology. Currently, new modern indicators found in the urine and serum are thought to be more informative biomarkers. In this paper, we investigated the effectiveness of some of them for possible potentials in the diagnostics of acute kidney injury in remote lithotripsy.
 AIM: To evaluate changes in acute kidney injury biomarkers during remote shock wave lithotripsy in children.
 MATERIALS AND METHODS: 54 children with urolithiasis, who had a session of remote shock wave lithotripsy, were enrolled in the study. In all patients, samples of urine and blood serum were taken three times for assessing biomarkers concentration: before lithotripsy session, after 45 min and after 24 h.
 RESULTS: Statistically significant changes in the concentration of all urine biomarkers (NGAL, L-FABP, TIMP-2, calbindin-D, KIM-1) were registered at the basal level and 45 min after the procedure. A number of markers studied by us in the blood serum showed more significant changes 24 h after the procedure (IL-18, TNF-α). Although IGFBP-1 concentration increased slightly after 45 min, this change was not statistically significant (p 0.781). The level of cystatin C did not increase after lithotripsy.
 CONCLUSION: The performed analysis of changes in biomarkers concentration has revealed a sufficiently high informative value of biomarkers in assessing the degree of acute kidney injury during remote lithotripsy in children. It also allows to suggest that the studied biomarkers may be promising indicators characterizing such an injury.

Exploring the Utility of Urinary Creatinine Adjustment for KIM-1, NGAL, and Cystatin C for the Assessment of Kidney Function: Insights from the C-KidnEES Cohort.

Normalization of urinary biomarkers of kidney injury is a common practice in clinical and research settings to account for variations in urine concentration, and urinary creatinine is often used as a reference. However, to date, there is no consensus on the adjustment of urinary biomarkers with creatinine, and both absolute and creatinine-adjusted biomarker levels are adopted for making interpretations of kidney health. Hence, the present study aimed to investigate the associations of urinary creatinine with three widely used kidney injury biomarkers, KIM-1, NGAL, and cystatin C, to validate the applicability of urinary creatinine as a reference for normalization. A cross-sectional study was performed with 2100 students, 10-18 years of age in the Children's Kidney Environmental Exposure Study (C-KidnEES) cohort established in Sri Lanka. As identified in linear regression analyses, normalization of urinary KIM-1, NGAL, and Cys-C to urinary creatinine did not result in significant under-adjustment or over-adjustment to the absolute urinary concentrations, giving no specific rationale for creatinine adjustment. Hence, absolute urinary concentrations of the above biomarkers can be adopted for the characterization of subclinical kidney injury in adolescents in community studies where early morning urine sampling is practiced. However, for spot urine samples, consideration of both absolute and creatinine-adjusted biomarker levels would be a better approach.

Precisely Constructing Renal-Clearable and LAP-Activatable Ratiometric Molecular Probes for Early Diagnosis of Acute and Chronic Kidney Injury Via Optimizing Asymmetric DPP Dyes.

Fluorescence analysis is an increasingly important contributor to the early diagnosis of kidney diseases. To achieve precise visualization of the kidneys and early diagnosis of related diseases, an asymmetric pyrrolopyrrolidone (DPP) dye platform with C-aromatic substituents and N-lipophilic/hydrophilic modification was constructed. Based on these, we developed the renal-clearable, water-soluble, and kidney injury biomarker leucine aminopeptidase (LAP) activated ratiometric fluorescent probe DPP-S-L. In the mouse model of cisplatin-induced acute kidney injury and during the development of type 2 diabetes to diabetic kidney disease, we visualized for the first time the upregulation of LAP in the kidney and urine by dual-channel ratiometric fluorescence signal and diagnosed the kidney injury earlier and more sensitively than blood/urine enzyme detection and tissue analysis. This study showcases an excellent asymmetric DPP dye platform and renal-clearable ratiometric fluorescent probe design strategy that is extended to determination and visualization of other biomarkers for early disease diagnosis.

Urinary biomarkers of early kidney injury in children with beta-thalassemia

Beta-thalassemia is considered as one of the most common genetic disorders in the world caused by the reduced or absent synthesis of b-globin chain. The aim of this work was to evaluate renal function in children with b-thalassemia using predictive biomarkers such as urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-b-D-glycosaminidase (NAG). This prospective case–control study was carried out on 80 subjects aged between 3 and 17 years. The subjects were divided into two equal groups: thalassemia group which included 40 children with b-thalassemia major, and control group which included 40 age- and gender-matched healthy, non-anemic controls without any diseases that could potentially affect renal function, who underwent routine check-ups. All thalassemia patients received chelation therapy: 35 (87.5%) of them were treated with deferasirox and 5 (12.5%) patients received deferasirox + deferoxamine. The results of echocardiography, kidney function tests (serum creatinine, urea and estimated glomerular filtration rate as well as urinary albumin/creatinine ratio and urinary NGAL/urinary albumin–creatinine ratio were insignificantly different between the two groups. Abdominal ultrasound findings were significantly different between both groups. Total WBC counts, platelet counts, the results of liver function tests (total bilirubin, direct bilirubin, alanine transaminase and aspartate aminotransferase), urinary NAG/creatinine ratios, urinary NGAL/creatinine ratios and serum ferritin levels were significantly higher in the thalassemia group, while hemoglobin, urinary NAG/urinary albumin–creatinine ratios were significantly lower in this group. Urinary markers NGAL and NAG could be used as predictive markers of renal disease in b-thalassemia major patients. The study was initiated after obtaining approval from the Ethical Committee of Menoufia University Hospital. Informed written consent was obtained from the parents of the children involved in the study.

Pre-clinical evaluation of biomarkers for the early detection of nephrotoxicity following alpha-particle radioligand therapy.

Cancer treatment with alpha-emitter-based radioligand therapies (α-RLTs) demonstrates promising tumor responses. Radiolabeled peptides are filtered through glomeruli, followed by potential reabsorption of a fraction by proximal tubules, which may cause acute kidney injury (AKI) and chronic kidney disease (CKD). Because tubular cells are considered the primary site of radiopeptides' renal reabsorption and potential injury, the current use of kidney biomarkers of glomerular functional loss limits the evaluation of possible nephrotoxicity and its early detection. This study aimed to investigate whether urinary secretion of tubular injury biomarkers could be used as an additional non-invasive sensitive diagnostic tool to identify unrecognizable tubular damage and risk of long-term α-RLT nephrotoxicity. A bifunctional cyclic peptide, melanocortin 1 ligand (MC1L), labeled with [203Pb]Pb-MC1L, was used for [212Pb]Pb-MC1L biodistribution and absorbed dose measurements in CD-1 Elite mice. Mice were treated with [212Pb]Pb-MC1L in a dose-escalation study up to levels of radioactivity intended to induce kidney injury. The approach enabled prospective kidney functional and injury biomarker evaluation and late kidney histological analysis to validate these biomarkers. Biodistribution analysis identified [212Pb]Pb-MC1L reabsorption in kidneys with a dose deposition of 2.8, 8.9, and 20 Gy for 0.9, 3.0, and 6.7 MBq injected [212Pb]Pb-MC1L doses, respectively. As expected, mice receiving 6.7 MBq had significant weight loss and CKD evidence based on serum creatinine, cystatin C, and kidney histological alterations 28 weeks after treatment. A dose-dependent urinary neutrophil gelatinase-associated lipocalin (NGAL, tubular injury biomarker) urinary excretion the day after [212Pb]Pb-MC1L treatment highly correlated with the severity of late tubulointerstitial injury and histological findings. Urine NGAL secretion could be a potential early diagnostic tool to identify unrecognized tubular damage and predict long-term α-RLT-related nephrotoxicity.

Environmental fluoride exposure and implications on potential pediatric kidney health risks: an approach with urinary biomarkers.

Environmental fluoride exposure at elevated levels is potentially linked to kidney injury, and may contribute to chronic kidney disease of uncertain etiology (CKDu) as a risk factor. However, this link remains unclear, and examining the risk of kidney damage from early life fluoride exposure may provide important insights. Hence, this study aimed to investigate associations of fluoride exposure with pediatric kidney health in CKDu impacted and unimpacted communities in Sri Lanka. Considering the geographical variations in environmental fluoride, climate, and prevalence of CKDu, four study groups were established within selected education zones in CKDu-endemic dry zone regions (D-En), and CKDu-nonendemic regions within the dry (D-NE), wet (W-NE), and intermediate (I-NE) climatic zones. The study population included 922 school students (11-18 years of age). Participants in each group were divided into four subgroups based on quartiles of respective urinary fluoride (UF) distribution for comparison of urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), and albumin-creatinine ratio (ACR). UF levels in participants particularly in CKDu endemic dry zone regions were significantly high compared to the other regions. Significantly high median urinary NGAL (in D-NE) and ACR (in D-EN, and W-NE) levels were observed in subgroups of higher UF quartiles. Albuminuria was not particularly identified in subjects with high UF excretion. Urinary KIM-1 showed no significant variation across the UF quartile subgroups. Linear regression identified weak associations of UF with kidney injury biomarkers. Fluoride exposure is particularly high in CKDu-endemic dry zone communities. As implied by kidney injury biomarkers, a strong link between fluoride exposure and pediatric kidney health was not evident at the observed exposure levels in the study regions.

Urinary Collectrin as Promising Biomarker for Acute Kidney Injury in Patients Undergoing Cardiac Surgery.

Early detection of acute kidney injury (AKI) is crucial for timely intervention and improved patient outcomes after cardiac surgery. This study aimed to evaluate the potential of urinary collectrin as a novel biomarker for AKI in this patient population. In this prospective, observational cohort study, 63 patients undergoing elective cardiac surgery with cardiopulmonary bypass (CPB) were studied at the Medical University of Vienna between 2016 and 2018. We collected urine samples prospectively at four perioperative time points, and urinary collectrin was measured using an enzyme-linked immunosorbent assay. Patients were divided into two groups, AKI and non-AKI, defined by Kidney Disease: Improving Global Outcomes Guidelines, and differences between groups were analyzed. Postoperative AKI was found in 19 (30%) patients. Urine sample analysis revealed an inverse correlation between urinary collectrin and creatinine and AKI stages, as well as significant changes in collectrin levels during the perioperative course. Baseline collectrin levels were 5050 ± 3294 pg/mL, decreased after the start of CPB, reached their nadir at the end of surgery, and began to recover slightly on postoperative day (POD) 1. The most effective timepoint for distinguishing between AKI and non-AKI patients based on collectrin levels was POD 1, with collectrin levels of 2190 ± 3728 pg/mL in AKI patients and 3768 ± 3435 pg/mL in non-AKI patients (p = 0.01). Urinary collectrin shows promise as a novel biomarker for the early detection of AKI in patients undergoing cardiac surgery on CPB. Its dynamic changes throughout the perioperative period, especially on POD 1, provide valuable insights for timely diagnosis and intervention. Further research and validation studies are needed to confirm its clinical usefulness and potential impact on patient outcomes.

Zoledronic acid and ibandronate-induced nephrotoxicity in 2D and 3D proximal tubule cells derived from human and rat.

Drug-induced proximal tubule (PT) injury remains a serious safety concern throughout drug development. Traditional in vitro 2-dimensional (2D) and preclinical in vivo models often fail to predict drug-related injuries presented in clinical trials. Various 3-dimensional (3D) microphysiological systems (MPSs) have been developed to mimic physiologically relevant properties, enabling them to be more predictive toward nephrotoxicity. To explore the capabilities of an MPS across species, we compared cytotoxicity in hRPTEC/TERT1s and rat primary proximal tubular epithelial cells (rPPTECs) following exposure to zoledronic acid and ibandronate (62.5-500 µM), and antibiotic polymyxin B (PMB) (50 and 250 µM, respectively). For comparison, we investigated cytotoxicity using 2D cultured hRPTEC/TERT1s and rPPTECs following exposure to the same drugs, including overlapping concentrations, as their 3D counterparts. Regardless of the in vitro model, bisphosphonate-exposed rPPTECs exhibited cytotoxicity quicker than hRPTEC/TERT1s. PMB was less sensitive toward nephrotoxicity in rPPTECs than hRPTEC/TERT1s, demonstrating differences in species sensitivity within both 3D and 2D models. Generally, 2D cultured cells experienced faster drug-induced cytotoxicity compared to the MPSs, suggesting that MPSs can be advantageous for longer-term drug-exposure studies, if warranted. Furthermore, ibandronate-exposed hRPTEC/TERT1s and rPPTECs produced higher levels of inflammatory and kidney injury biomarkers compared to zoledronic acid, indicating that ibandronate induces acute kidney injury, but also a potential protective response since ibandronate is less toxic than zoledronic acid. Our study suggests that the MPS model can be used for preclinical screening of compounds prior to animal studies and human clinical trials.

Choroidal and retinal thinning in chronic kidney disease independently associate with eGFR decline and are modifiable with treatment

In patients with chronic kidney disease (CKD), there is an unmet need for novel biomarkers that reliably track kidney injury, demonstrate treatment-response, and predict outcomes. Here, we investigate the potential of retinal optical coherence tomography (OCT) to achieve these ends in a series of prospective studies of patients with pre-dialysis CKD (including those with a kidney transplant), patients with kidney failure undergoing kidney transplantation, living kidney donors, and healthy volunteers. Compared to health, we observe similar retinal thinning and reduced macular volume in patients with CKD and in those with a kidney transplant. However, the choroidal thinning observed in CKD is not seen in patients with a kidney transplant whose choroids resemble those of healthy volunteers. In CKD, the degree of choroidal thinning relates to falling eGFR and extent of kidney scarring. Following kidney transplantation, choroidal thickness increases rapidly (~10%) and is maintained over 1-year, whereas gradual choroidal thinning is seen during the 12 months following kidney donation. In patients with CKD, retinal and choroidal thickness independently associate with eGFR decline over 2 years. These observations highlight the potential for retinal OCT to act as a non-invasive monitoring and prognostic biomarker of kidney injury.

LC/MS-MS quantification of myo-inositol: a novel biomarker for kidney disease

Abstract Creatinine is the primary biomarker used for assessing kidney function in patients with suspected acute and chronic kidney injury. However, creatinine, a product of muscle creatine metabolism, is an imperfect proxy for renal function because it is subject to non-renal interferences including muscle mass, diet, and medications. Creatinine is particularly problematic as a biomarker of acute kidney injury (AKI) due to relatively high renal function reserve, requiring considerable kidney damage and time for a clinically significant change in creatinine to be detected. Given that AKI and chronic kidney injury (CKD) are associated with high mortality, morbidity, and contribute significantly to health care costs, there is an unmet need for highly sensitive and specific biomarkers for assessing renal function in patients. Myo-inositol oxygenase (MIOX) is a novel biomarker limitedly expressed in the proximal renal tubules. MIOX concentrations are elevated in mice with renal injury and in critically ill patients with AKI. Our previously published studies have demonstrated that elevation in MIOX concentrations precedes changes in creatinine concentrations by approximately 54 hours. Importantly, MIOX facilitates the conversion of myo-inositol to glucuronic acid. We developed a robust LC-MS/MS method to quantify myo-inositol in human plasma, hypothesizing that following renal injury (acute and chronic), plasma concentrations of myo-inositol will increase, and will correlate with increases in serum creatinine concentrations. A healthy outpatient cohort was identified from samples obtained from out-patients with normal plasma creatinine, eGFR>60, as well as normal urine protein: creatinine ratio, albumin: creatinine ratio, or urinalysis results that were pan-negative/pan-normal. Remnant samples from out-patients with clinically staged CKD who have not initiated dialyses were selected for the CKD group. In healthy adult out-patients with stable renal function, the central 95th% distribution of plasma myo-inositol concentrations was 16.61 - 44.2 uM (Median 27.7uM, 95% CI: 26.7-28-7). No sex-based differences in plasma myo-inositol were observed. We also observed excellent correlation between plasma myo-inositol and serum creatinine concentrations (r=0.84, 95% CI: 80-88), as well as excellent sensitivity (99%) and specificity (100%) at a myo-inositol concentration of 50.22uM for differentiating patients with stable kidney function from those with CKD. Patients with CKD exhibited higher plasma myo-inositol concentrations (p value <0.0001) with a central 95% percentile of 51.2-309.1 uM (Median 104.1 uM, 95% CI: 92.3- 113.6). These results imply that myo-inositol concentrations increase in accord with renal injury and MIOX buildup in patients with kidney dysfunction, making it a potential biomarker for renal impairment.

Hemodynamics and urinary excretion of kidney-injury biomarkers in pediatric kidney transplantation.

Hemodynamics and urinary excretion of kidney-injury biomarkers in pediatric kidney transplantation.