Development of Liver Fibrosis Represented by the Fibrosis-4 Index Is a Specific Risk Factor for Tubular Injury in Individuals with Type 2 Diabetes.

Although hyperglycemia and hypertension are well-known risk factors for glomerular injury in individuals with type 2 diabetes (T2D), specific risk factors for tubular injury remain unclear. We aimed to clarify the differences between risk factors for glomerular injury and risk factors for tubular injury in individuals with T2D. We categorized 1243 subjects into four groups based on urinary biomarkers, including the albumin-to-creatinine ratio (uACR) and L-type fatty acid-binding protein-to-creatinine ratio (uL-ABPCR) as a normal (N) group (uACR < 30 mg/gCr and uL-FABPCR < 5 µg/gCr; n = 637), a glomerular specific injury (G) group (uACR ≥ 30 mg/gCr and uL-FABPCR < 5 µg/gCr; n = 248), a tubular specific injury (T) group (uACR < 30 mg/gCr and uL-FABPCR ≥ 5 µg/gCr; n = 90), and a dual injury (D) group (uACR ≥ 30 mg/gCr and uL-FABPCR ≥ 5 µg/gCr; n = 268). Logistic regression analysis referencing the N group revealed that BMI, current smoking, and hypertension were risk factors for the G group, creatinine (Cr) and Fibrosis-4 (FIB-4) index were risk factors for the T group, and BMI, hypertension, HbA1c, Cr, and duration of diabetes were risk factors for the D group. While hypertension was a distinct specific risk factor for glomerular injury, the FIB-4 index was a specific contributor to the prevalence of tubular injury. On the other hand, the logistic regression analysis revealed that the hepatic steatosis index (HSI) did not show any significant association with the G group, T group, or D group. Taken together, the development of liver fibrosis rather than liver steatosis is an inherent threat relating to tubular injury in individuals with T2D.

Evaluation of Urinary L-FABP as a Tubular Damage Marker in Pediatric Neurogenic Bladder-A Pilot Study.

The article aims to find potential biomarker for the detection of tubular damage in pediatric neurogenic bladder (NB) by investigating urinary levels of liver-type fatty acid-binding protein (uL-FABP). This prospective analysis was conducted on two groups: 42 children with NB and 18 healthy children. The uL-FABP concentrations were measured using ELISA methods. The medical charts of the children were examined to determine age, sex, anthropometric measurements, activity assessment using Hoffer's scale, and renal function parameters. The results revealed that the uL-FABP/creatinine ratio was higher in the study group compared with the reference group, but the difference was not statistically significant (p = 0.52, p > 0.05). However, the uL-FABP/creatinine ratio exhibited a wider range in NB patients compared to the reference group. NB children with proteinuria and the history of high-grade vesicoureteral reflux (VUR) tended to have the highest uL-FABP concentrations. In conclusion, uL-FABP may be considered a potential tubular damage biomarker in children with NB. Proteinuria and the history of VUR may be the factors influencing the uL-FABP.

Urine oxygenation predicts COVID-19 risk.

Since February, 2023, the omicron variant has accounted for essentially all new coronavirus infections in Japan. If future infections involve mutant strains with the same level of infectivity and virulence as omicron, the government's basic policy will be to prevent the spread of infection, without compromising socioeconomic activities. Objectives include protecting pregnant women and elderly persons, and focusing on citizens requiring hospitalization and those at risk of serious illness, without imposing new social restrictions. Although the government tries to raise public awareness through education, most people affected by COVID-19 stay at home, and by the time patients become aware of the seriousness of their disease, it has often reached moderate or higher severity. In this review, we discuss why this situation persists even though the disease seems to have become milder with the shift from the delta variant to omicron. We also propose a pathophysiological method to determine the risk of severe illness. This assessment can be made at home in the early stages of COVID-19 infection, using urine analysis. Applicability of this method to drug discovery and development is also discussed.

Urinary liver-type fatty acid binding protein is a biomarker reflecting renal damage and the ameliorative effect of drugs at an early stage of histone-induced acute kidney injury.

AIM: Circulated histones play a crucial role in the pathogenesis of infectious diseases and severe trauma, and it is one of the potential molecular targets for therapeutics. Recently, we reported that histone is one of the causative agents for urinary L-FABP increase. However, the mechanism is still unclear, especially in severe cases. We further investigated the mechanism of urinary L-FABP increase using a more severe mouse model with histone-induced kidney injury. This study also aims to evaluate the therapeutic responsiveness of urinary L-FABP as a preliminary study. METHODS: Human L-FABP chromosomal transgenic mice were administrated 30 mg/kg histone from a tail vein with a single dose. We also performed a comparative study in LPS administration model. For the evaluation of the therapeutic responsiveness of urinary L-FABP, we used heparin and rolipram. RESULTS: The histological change with cast formation as a characteristic of the models was observed in proximal tubules. Urinary L-FABP levels were significantly elevated and these levels tended to be higher in those with more cast formation. Heparin and rolipram had the ameliorative effect of the cast formation induced by histone and urinary L-FABP levels significantly decreased. CONCLUSION: Histone is one of the causative agents for the increase of urinary L-FABP at an early stage of AKI. In addition, it suggested that urinary L-FABP may be useful as a subclinical AKI marker reflecting kidney damage induced by histone. Furthermore, urinary L-FABP reflected the degree of the damage after the administration of therapeutic agents such as heparin and PDE4 inhibitor.

Cross-Sectional and Longitudinal Associations between Skin Autofluorescence and Tubular Injury Defined by Urinary Excretion of Liver-Type Fatty Acid-Binding Protein in People with Type 2 Diabetes.

It has previously been unclear whether the accumulation of advanced glycation end products, which can be measured using skin autofluorescence (SAF), has a significant role in diabetic kidney disease (DKD), including glomerular injury and tubular injury. This study was therefore carried out to determine whether SAF correlates with the progression of DKD in people with type 2 diabetes (T2D). In 350 Japanese people with T2D, SAF values were measured using an AGE Reader®, and both urine albumin-to-creatinine ratio (uACR), as a biomarker of glomerular injury, and urine liver-type fatty acid-binding protein (uLFABP)-to-creatinine ratio (uL-FABPCR), as a biomarker of tubular injury, were estimated as indices of the severity of DKD. Significant associations of SAF with uACR (p < 0.01), log-transformed uACR (p < 0.001), uL-FABPCR (p < 0.001), and log-transformed uL-FABPCR (p < 0.001) were found through a simple linear regression analysis. Although SAF was positively associated with increasing uL-FABPCR (p < 0.05) and increasing log-transformed uL-FABPCR (p < 0.05), SAF had no association with increasing uACR or log-transformed uACR after adjusting for clinical confounding factors. In addition, the annual change in SAF showed a significant positive correlation with annual change in uL-FABPCR regardless of confounding factors (p = 0.026). In conclusion, SAF is positively correlated with uL-FABP but not with uACR in people with T2D. Thus, there is a possibility that SAF can serve as a novel predictor for the development of diabetic tubular injury.

Disclosing Environmental Ligands of L-FABP and PPARγ: Should We Re-evaluate the Chemical Safety of Hydrocarbon Surfactants?

Chemical contaminants can cause adverse effects by binding to the liver-fatty acid binding protein (L-FABP) and peroxisome proliferator-activated nuclear receptor γ (PPARγ), which are vital in lipid metabolism. However, the presence of numerous compounds in the environment has hindered the identification of their ligands, and thus only a small portion have been discovered to date. In this study, protein Affinity Purification with Nontargeted Analysis (APNA) was employed to identify the ligands of L-FABP and PPARγ in indoor dust and sewage sludge. A total of 83 nonredundant features were pulled-out by His-tagged L-FABP as putative ligands, among which 13 were assigned as fatty acids and hydrocarbon surfactants. In contrast, only six features were isolated when His-tagged PPARγ LBD was used as the protein bait. The binding of hydrocarbon surfactants to L-FABP and PPARγ was confirmed using both recombinant proteins and reporter cells. These hydrocarbon surfactants, along with >50 homologues and isomers, were detected in dust and sludge at high concentrations. Fatty acids and hydrocarbon surfactants explained the majority of L-FABP (57.7 ± 32.9%) and PPARγ (66.0 ± 27.1%) activities in the sludge. This study revealed hydrocarbon surfactants as the predominant synthetic ligands of L-FABP and PPARγ, highlighting the importance of re-evaluating their chemical safety.

Hepatotoxicity assessment investigations on PFASs targeting L-FABP using binding affinity data and machine learning-based QSAR model.

Per- and polyfluoroalkyl substances (PFASs) are persistent organic pollutants that have been detected in various environmental media and human serum, but their safety assessment remains challenging. PFASs may accumulate in liver tissues and cause hepatotoxicity by binding to liver fatty acid binding protein (L-FABP). Therefore, evaluating the binding affinity of PFASs to L-FABP is crucial in assessing the potential hepatotoxic effects. In this study, two binding sites of L-FABP were evaluated, results suggested that the outer site possessed high affinity to polyfluoroalkyl sulfates and the inner site preferred perfluoroalkyl sulfonamides, overall, the inner site of L-FABP was more sensitive to PFASs. The binding affinity data of PFASs to L-FABP were used as training set to develop a machine learning model-based quantitative structure-activity relationship (QSAR) for efficient prediction of potentially hazardous PFASs. Further Bayesian Kernel Machine Regression (BKMR) model disclosed flexibility as the determinant molecular property on PFASs-induced hepatotoxicity. It can influence affinity of PFASs to target protein through affecting binding conformations directly (individual effect) as well as integrating with other molecular properties (joint effect). Our present work provided more understanding on hepatotoxicity of PFASs, which could be significative in hepatotoxicity gradation, administration guidance, and safer alternatives development of PFASs.

Urinary liver-type fatty acid binding protein is increased in the early stages of the disease with a risk of acute kidney injury induced by histone.

AIM: Urinary liver-type fatty acid binding protein (L-FABP) has potential utility as an early prognostic biomarker ahead of traditional severity scores in coronavirus disease 2019 and sepsis, however, the mechanism of elevated urinary L-FABP in the disease has not been clearly elucidated. We investigated the background mechanisms of urinary L-FABP excretion through non-clinical animal model focusing on histone, which is one of the aggravating factors in these infectious diseases. METHODS: Male Sprague-Dawley rats were placed in central intravenous catheters, and these rats were given a continuous intravenous infusion of 0.25 or 0.5 mg/kg/min calf thymus histones for 240 min from caudal vena cava. RESULTS: After the administration of histone, urinary L-FABP and gene expression of an oxidative stress marker in the kidney increased in a histone dose-dependent manner before increased serum creatinine. Upon further investigation, fibrin deposition in the glomerulus was observed and it tended to be remarkable in the high dose administrated groups. The levels of coagulation factor were significantly changed after the administration of histone, and these were significantly correlated with the levels of urinary L-FABP. CONCLUSIONS: Firstly, it was suggested that histone is one of the causative agents for the urinary L-FABP increase at an early stage of the disease with a risk of acute kidney injury. Secondly, urinary L-FABP could be a marker reflecting the changes of coagulation system and microthrombus caused by histone in the early stage of acute kidney injury before becoming severely ill and maybe a guide to early treatment initiation.

Interleukin-18 and Gelsolin Are Associated with Acute Kidney Disease after Cardiac Catheterization.

Patients undergoing cardiac catheterization are at high risk of post-procedure acute kidney injury (AKI) and may experience persistent renal damage after an initial insult, a state known as acute kidney disease (AKD). However, the association between AKD and urinary renal biomarkers has not yet been evaluated in this population. We enrolled 94 patients who underwent elective cardiac catheterization to investigate patterns of urinary renal biomarkers and their associations with post-procedure AKD. Serial urinary renal biomarker levels were measured during pre-procedure, early post-procedure (12-24 h), and late post-procedure (7-10 days) periods. In our investigation, 42.55% of the enrolled patients developed AKD during the late post-procedure period. While the liver-type free-fatty-acid-binding protein level increased sharply during the early post-procedure period, it returned to baseline during the late post-procedure period. In contrast, interleukin-18 (IL-18) levels increased steadily during the post-procedure period. Early post-procedure ratios of IL-18 and gelsolin (GSN) were independently associated with subsequent AKD (odds ratio (95% confidence interval), 4.742 (1.523-14.759) for IL-18 ratio, p = 0.007; 1.812 (1.027-3.198) for GSN ratio, p = 0.040). In conclusion, post-procedure AKD is common and associated with early changes in urinary IL-18 and GSN in patients undergoing cardiac catheterization.

Rapid and ultrasensitive detection of acute kidney injury biomarkers CH3L1 and L-FABP using surface-enhanced Raman spectroscopy.

Chitinase 3-like 1 (CH3L1) and liver fatty acid binding protein (L-FABP) are promising biomarkers for the early diagnosis of acute kidney injury (AKI). Here, a highly sensitive method for the quantitative detection of CH3L1 and L-FABP by surface-enhanced Raman spectroscopy (SERS) based on graphene oxide/gold and silver core-shell nanoparticles (GO/Au@Ag NPs) was proposed. The results showed that such GO/Au@Ag substrate can achieve rapid sensing of CH3L1 and L-FABP with a wide response range (2 × 10-1 to 2 × 10-8 mg/mL and 1.2 × 10-1 to 1.2 × 10-8 mg/mL, respectively) and high sensitivity. The detection limits of CH3L1 and L-FABP were 1.21 × 10-8 mg/mL and 0.62 × 10-8 mg/mL, respectively. In addition, the simultaneous detection of the two biomarkers in serum was demonstrated, showing the feasibility of this method in the complex biological environment. The detection of CH3L1 and L-FABP will greatly improve the early diagnosis and intervention of AKI.

Association of urinary liver-type fatty acid-binding protein with renal functions and antihyperglycemic drug use in type 2 diabetic nephropathy patients.

PURPOSE: In diabetic nephropathy exacerbation, a reduction in the estimated glomerular filtration rate (eGFR) without raised albuminuria or proteinuria has been frequently observed. This study aimed to clarify the clinical usefulness of urinary liver-type fatty acid-binding protein (L-FABP) in the exacerbation of diabetic nephropathy in type 2 diabetes. METHODS: A cross-sectional study and a retrospective observational study of 227 patients with type 2 diabetes were conducted to investigate the relationship between urinary L-FABP and renal dysfunction. Changes in urinary L-FABP with or without additional administration of antihyperglycemic drugs were examined in 63 patients. RESULTS: Baseline urinary L-FABP was significantly associated with baseline eGFR (ρ = -0.34, p < 0.001) and baseline albuminuria (ρ = 0.64, p < 0.001). In multivariate regression analysis, baseline urinary L-FABP was a significant independent factor for eGFR reduction [ß = -0.348, 95% confidence interval (CI) = -0.482 to -0.214, p < 0.001]. Cox regression analysis showed that patients with a baseline urinary L-FABP above 6.5 µg/g creatinine exhibited a higher hazard ratio (HR) for the renal dysfunction surrogate end point (HR = 15.00, 95% CI 3.640-61.40, p < 0.001). In logistic regression analysis, administration of sodium glucose cotransporter-2 inhibitors was associated with a statistically significant reduction in urinary L-FABP levels, independent of changes in systolic blood pressure, glycosylated hemoglobin, and eGFR (odds ratio = 0.75, 95% CI 0.56-0.99, p = 0.04). CONCLUSION: Urinary L-FABP may be associated with the future decrease in renal functions in type 2 diabetic nephropathy patients. Additionally, urinary L-FABP could be used as a marker of the effectiveness of diabetic nephropathy treatment.

Markers of Kidney Tubular Function Deteriorate While Those of Kidney Tubule Health Improve in Primary Aldosteronism After Targeted Treatments.

Background Targeted treatment with mineralocorticoid receptor antagonists (MRAs) or adrenalectomy in patients with primary aldosteronism (PA) causes a decline in estimated glomerular filtration rate; however, the associated simultaneous changes in biomarkers of kidney tubule health still remain unclear. Methods and Results We matched 104 patients with newly diagnosed unilateral PA who underwent adrenalectomy with 104 patients with unilateral PA who were treated with MRAs, 104 patients with bilateral PA treated with MRAs, and 104 patients with essential hypertension who served as controls. Functional biomarkers were measured before the targeted treatment and 1 year after treatment, including serum markers of kidney function (cystatin C, creatinine), urinary markers of proximal renal tubular damage (L-FABP [liver-type fatty-acid binding protein], KIM-1 [kidney injury molecule-1]), serum markers of kidney tubular reserve and mineral metabolism (intact parathyroid hormone), and proteinuria. Compared with the patients with essential hypertension, the patients with PA had higher pretreatment serum intact parathyroid hormone and urinary creatinine-corrected parameters, including L-FABP, KIM-1, and albumin. The patients with essential hypertension and with PA had similar cystatin C levels. After treatment with MRAs or adrenalectomy of unilateral PA and MRAs of bilateral PA, the patients with PA had increased serum cystatin C and decreased urinary L-FABP/creatinine, KIM-1/creatinine, creatinine-based estimated glomerular filtration rate, intact parathyroid hormone, and proteinuria (all P<0.05). In multivariable regression models, a higher urinary L-FABP/creatinine ratio and older age were significantly correlated with the occurrence of kidney failure (estimated glomerular filtration rate dip ≥30%) in the patients with PA after targeted treatment. Conclusions Compared with the matched patients with essential hypertension, the incident patients with PA at diagnosis had higher levels of several biomarkers, including markers of kidney damage, tubular reserve/mineral metabolism, and proteinuria. Functional kidney failure in the patients with PA after treatment could be predicted by a higher baseline urinary L-FABP/creatinine ratio and older age. After targeted treatments in the patients with bilateral or unilateral PA, these biomarkers of kidney tubule health were restored, but creatinine-based estimated glomerular filtration rate declined, which may therefore reflect hemodynamic changes rather than intrinsic damage to kidney tubular cells.

L-FABP and NGAL are novel biomarkers for detection of abdominal injury and hemorrhagic shock.

INTRODUCTION: Delayed diagnosis of abdominal injuries and hemorrhagic shock leads to secondary complications and high late mortality in severely traumatized patients. The liver fatty acid-binding protein (L-FABP) is expressed in intestine, liver and kidney; the neutrophil gelatinase-associated lipocalin (NGAL) in colon and kidney. We hypothesized that l-FABP is an early biomarker for abdominal injury and hemorrhagic shock and that l-FABP and NGAL are specific markers for detection of liver and/or kidney injuries. PATIENTS AND METHODS: Traumatized patients with an age ≥18 years and an abdominal injury (AISabd≥2), independently from Injury Severity Score (ISS), were prospectively included from 04/2018 to 05/2021. 68 patients had an abdominal injury ("Abd") and 10 patients had an abdominal injury with hemorrhagic shock ("HS Abd"). 41 patients without abdominal injury and hemorrhagic shock but with an ISS ≥ 25 ("noAbd") were included as control group. Four abdominal subgroups with isolated organ injuries were defined. Plasma l-FABP and NGAL levels were measured at admission (ER) and up to two days post-trauma. RESULTS: All patient groups had a median ISS≥25. In ER, median l-FABP levels were significantly higher in "HS Abd" group (1209.2 ng/ml [IQR=575.2-1780.3]) compared to "noAbd" group (36.4 ng/ml [IQR=14.8-88.5]), and to "Abd" group (41.4 ng/ml [IQR=18.0-235.5]), p<0.001. In matched-pair-analysis l-FABP levels in the group "Abd" were significantly higher (108.3 ng/ml [IQR=31.4-540.9]) compared to "noAbd" (26.4 ng/ml [IQR=15.5-88.8]), p = 0.0016. l-FABP correlated significantly with clinical parameters of hemorrhagic shock; the optimal cut-off level of l-FABP for detection was 334.3 ng/ml (sensitivity: 90%, specificity: 78%). Median l-FABP-levels were significantly higher in patients with isolated liver or kidney injuries and correlated significantly with AST, ALT and creatinine value. Median NGAL levels in the ER were significantly higher in "HS Abd" group (115.9 ng/ml [IQR=90.6-163.8]) compared to "noAbd" group (58.5 ng/ml [IQR=41.0-89.6],p<0.001) and "Abd" group (70.5 ng/ml [IQR=53.3-115.5], p<0.05). The group "Abd" showed significant higher median NGAL levels compared to "noAbd", p = 0.019. NGAL levels correlated significantly with clinical parameters of hemorrhagic shock. CONCLUSION: L-FABP and NGAL are novel biomarkers for detection of abdominal trauma and hemorrhagic shock. l-FABP may be a useful and promising parameter in diagnosis of liver and kidney injuries, NGAL failed to achieve the same.

Early biomarkers for kidney injury in heat-related illness patients: a prospective observational study at Japanese Self-Defense Force Fuji Hospital.

BACKGROUND: Since heatstroke-induced acute kidney injury (AKI) can progress to chronic kidney disease, it would be useful to detect heatstroke-induced AKI and severe heat-related illness in the early phase. We studied the epidemiology of heat-related illness among patients in the Japanese Ground Self-Defense Force and evaluated the relationship between heat-related illness severity and early urinary biomarkers for AKI. METHODS: We enrolled patients who were diagnosed with heat-related illness at the Self-Defense Force Fuji Hospital from 1 May to 30 September 2020. We compared the urinary kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and ß2-microglobulin levels according to the severity of heat-related illness as defined by positive scores for the Japanese Association of Acute Medicine Heatstroke Working Group (JAAM-HS-WG) criteria (0, mild; 1, moderate; ≥2, severe). RESULTS: Of the 44 patients, kidney injury, defined as serum creatinine (sCr) ≥1.2 mg/dL, was seen in 9 (20.5%) patients. Urinary NAG, NGAL and L-FABP levels were significantly higher in the ≥2 JAAM-HS-WG criteria group than in the 0 group. Furthermore, urinary L-FABP levels were positively correlated with sCr levels. In contrast, the urinary KIM-1 levels showed the best correlation with serum cystatin C (sCysC) among these biomarkers. CONCLUSIONS: We conclude even mild to moderate heatstroke could lead to AKI. Urinary L-FABP is useful for detecting heatstroke-induced AKI and patients with severe heat-related illness requiring immediate treatment. Urinary KIM-1 may detect heatstroke-induced AKI in terms of sCysC, although it was not related to the severity of heat-related illness.

Utility of urinary liver-type fatty acid-binding protein as a prognostic marker in adult congenital heart patients hospitalized for acute heart failure.

Progression to acute kidney injury (AKI) under treatment in adult congenital heart disease (ACHD) patients with heart failure is associated with poor prognosis, early detection and interventions are necessary. We aimed to explore the utility of urinary liver-type fatty acid binding protein (L-FABP) in ACHD patients hospitalized for acute decompensated heart failure (ADHF). We prospectively evaluated hemodynamic, biochemical data, and urinary biomarkers including urinary L-FABP in ACHD patients hospitalized in our institution from June 2019 to March 2022. The primary outcomes were the development of AKI and death. AKI was defined as serum creatinine level increased by 0.3 mg/dl or more within 5 days after hospitalization. A total of 104 ADHF patients aged 31 (36-51) years were enrolled. 26 cases (25% of ADHF patients) developed AKI during hospitalization and 4 died after hospital discharge. Serum creatinine (sCr), serum total bilirubin, brain natriuretic peptide (BNP), and urinary L-FABP in AKI patients were significantly higher than in non-AKI patients, whereas systemic oxygen saturation of the peripheral artery (SpO2) and estimated glomerular filtration ratio in AKI patients were lower than non-AKI patients. There was no difference in the intravenous diuretic dose on admission and during hospitalization between the two groups. In the receiver operating characteristic (ROC) analysis, the maximum area under the curve (AUC) of urinary biomarkers in AKI patients was urinary L-FABP (AUC = 0.769, p < 0.001) with a cutoff value of 4.86 µg/gCr. Urinary L-FABP level on admission was associated with a predictor for AKI development during hospitalization after adjusting for sCr, BNP and SpO2. Urinary L-FABP was a useful predictor for the development of AKI in ACHD patients hospitalized for ADHF. Monitoring of urinary L-FABP allows us to detect a high-risk patient earlier than the conventional biomarkers.

Urinary liver-type fatty acid-binding protein in clinically healthy elderly cats: Evaluation of its potential to detect IRIS stage 1 chronic kidney disease and borderline proteinuria.

BACKGROUND: Urinary liver-type fatty acid-binding protein (uL-FABP) is a promising biomarker to detect early chronic kidney disease (CKD) in cats. Few healthy cats show increased uL-FABP for unknown reasons. OBJECTIVES: The objective of this study was to evaluate uL-FABP in a large healthy elderly cat population comparing cats with and without International Renal Interest Society (IRIS) stage 1 CKD and with and without borderline proteinuria. METHODS: This was a cross-sectional study. One hundred ninety-six clinically healthy client-owned cats of ≥7 years old were subdivided based on two criteria: (1) having either IRIS stage 1 CKD or no evidence of CKD and (2) having borderline proteinuria or no proteinuria. Urinary L-FABP was measured using a validated commercially available feline L-FABP ELISA. RESULTS: Overall, uL-FABP was detectable in 6/196 (3%) healthy elderly cats. For the first subdivision, nine (5%) cats had IRIS stage 1 CKD, 184 cats had no evidence CKD and three cats were excluded. All cats with IRIS stage 1 CKD had uL-FABP concentrations below the detection limit, whereas 6/184 (3%) cats without IRIS stage 1 CKD had detectable uL-FABP concentrations (median 1.79 ng/ml, range 0.79-3.66 ng/ml). For the second subdivision, 47 (24%) cats had borderline proteinuria, 147 cats had no proteinuria and two cats were excluded. One of the borderline proteinuric cats had a detectable uL-FABP concentration, whereas the other five cats with detectable uL-FABP concentrations were non-proteinuric. CONCLUSION: With the current assay, the screening potential of uL-FABP as an early biomarker for feline CKD is limited as uL-FABP was rarely detected in clinically healthy elderly cats independently of the presence of either IRIS stage 1 CKD or borderline proteinuria.

Predictive markers in chronic kidney disease.

Chronic kidney disease (CKD) is defined by gradual deterioration of the renal parenchyma and decline of functioning nephrons. CKD is now recognized as a distinct risk factor for cardiovascular disease (CVD). This risk rises in tandem with the decline in kidney function and peaks at the end-stage. It is important to identify individuals with CKD who are at a higher risk of advancing to end-stage renal disease (ESRD) and the beginning of CVD. This will enhance the clinical benefits and so that evidence-based therapy may be started at the initial stages for those individuals. A promising biomarker must represent tissue damage, and be easy to detect using non-invasive methods. Current CKD progression indicators have difficulties in reaching this aim. Hence this review presents an update on markers studied in the last decade, which help in the prediction of CKD progression such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, urinary liver-type fatty acid-binding protein, cystatin-C, asymmetric dimethylarginine, symmetric dimethylarginine, endotrophin, methylglyoxal, sclerostin, uric acid, and miRNA-196a. Additional research is needed to determine the predictive usefulness of these indicators in clinical samples for disease development. Their utility as surrogate markers need to be explored further for the early identification of CKD progression.

Biomarkers for Detecting Kidney Dysfunction in Type-2 Diabetics and Diabetic Nephropathy Subjects: A Case-Control Study to Identify Potential Biomarkers of DN to Stratify Risk of Progression in T2D Patients.

Introduction: Currently there are no biomarkers that are predictive of when patients with type-2 diabetes (T2D) will progress to more serious kidney disease i.e., diabetic nephropathy (DN). Biomarkers that could identify patients at risk of progression would allow earlier, more aggressive treatment intervention and management, reducing patient morbidity and mortality. Materials and Methods: Study participants (N=88; control n=26; T2D n=32; DN n=30) were recruited from the renal unit at Antrim Area Hospital, Antrim, UK; Whiteabbey Hospital Diabetic Clinic, Newtownabbey, UK; Ulster University (UU), Belfast, UK; and the University of the Third Age (U3A), Belfast, UK; between 2019 and 2020. Venous blood and urine were collected with a detailed clinical history for each study participant. Results: In total, 13/25 (52.0%) biomarkers measured in urine and 25/34 (73.5%) biomarkers measured in serum were identified as significantly different between control, T2D and DN participants. DN patients, were older, smoked more, had higher systolic blood pressure and higher serum creatinine levels and lower eGFR function. Serum biomarkers significantly inversely correlated with eGFR. Conclusion: This pilot-study identified several serum biomarkers that could be used to predict progression of T2D to more serious kidney disease: namely, midkine, sTNFR1 and 2, H-FABP and Cystatin C. Our results warrant confirmation in a longitudinal study using a larger patient cohort.

Fractional Excretion of Sodium and Urea in Differentiating Acute Kidney Injury Phenotypes in Decompensated Cirrhosis.

Background: Prerenal acute kidney injury (prerenal AKI), hepatorenal syndrome (HRS-AKI), and acute tubular necrosis (ATN-AKI) are the various phenotypes of acute kidney injury, which are described in decompensated cirrhosis. It has therapeutic and prognostic implications. We aimed to evaluate the diagnostic utility of fractional excretion of sodium and urea (FENa and FEUrea) for differentiating AKI phenotypes. Methods: A prospective analysis was performed in 200 patients with decompensated cirrhosis with AKI to derive receiver operating curve, optimal cut-off, sensitivity, and specificity. These findings were validated in an independent cohort (n = 50) to differentiate ATN-AKI, HRS-AKI, and prerenal AKI. Results: The incidence of prerenal AKI, HRS-AKI, and ATN-AKI were 37.5%, 34%, and 28.5% in the derivation cohort and 28%, 38%, and 34% in the validation cohort respectively. The median FENa was significantly different in various phenotypes of AKI in the derivation and validation cohort (P 0.001); FEUrea was significantly different in the derivation cohort (P 0.0001), not in the validation cohort (P 0.106). The AUC for FENa (cut-off, sensitivity/specificity) was 86.6% (0.567, 89/71) and for FEUrea was 60.3% (34.73, 70/58) for ATN-AKI vs. non-ATN-AKI. The area under the curve for FENa to differentiate between HRS-AKI vs. non-HRS-AKI was 74.5%. FEUrea could not differentiate HRS-AKI vs. non-HRS-AKI (AUC 60.4%) satisfactorily. FENa and FEUrea were unable to differentiate between prerenal AKI and HRS-AKI (AUC <70%). Conclusion: Among cirrhotics FENa at admission is a simple, commonly available clinical tool that can be used to differentiate structural AKI from prerenal AKI and HRS-AKI. The newly derived lowered cut-off value of FENa makes the diagnosis of ATN-AKI easier, faster and thus obviates the need for extensive workup in a significant proportion of patients. FENa appears better than FEUrea in decompensated cirrhosis with AKI.

Insights into the Competitive Mechanisms of Per- and Polyfluoroalkyl Substances Partition in Liver and Blood.

Some per- and polyfluoroalkyl substances (PFASs) tend to be accumulated in liver and cause hepatotoxicity. However, the difficulty to directly measure liver concentrations of PFASs in humans hampers our understanding of their hepatotoxicity and mechanisms of action. We investigated the partitioning of 11 PFASs between liver and blood in male CD-1 mice. Although accumulation of the perfluoroalkanesulfonic acids (PFSAs) in mice serum was higher than their carboxylic acids (PFCAs) counterparts as expected, the liver-blood partition coefficients (RL/S) of PFSAs were lower than the PFCAs RL/S, implying a competition between liver and blood. The in vitro experiments further indicated that the partitioning was dominantly determined by their competitive binding between human liver fatty acid binding protein (hL-FABP) and serum albumin (HSA). The binding affinities (Kd) of PFASs to both proteins were measured. The correlations between the RL/S and log Kd (hL-FABP)/log Kd (HSA) were stronger than those with log Kd (hL-FABP) alone, magnifying that the partitioning was dominantly controlled by competitive binding between hL-FABP and HSA. Therefore, the liver concentrations of the selected PFASs in humans could be predicted from the available serum concentrations, which is important for assessing their hepatotoxicity.