Liver-type Fatty Acid-binding Protein Research Articles

Potential Prognostic Markers of Acute Kidney Injury in the Early Phase of Acute Pancreatitis.

Acute kidney injury (AKI) is a serious complication of acute pancreatitis (AP), which occurs in up to 70% of patients with severe AP and significantly increases the risk of mortality. At present, AKI is diagnosed based on dynamic increase in serum creatinine and decreased urine output; however, there is a need for earlier and more accurate biomarkers. The aim of the study was to review current evidence on the laboratory tests that were studied as the potential biomarkers of AKI in AP. We also briefly summarized the knowledge coming from the studies including sepsis or ICU patients since severe acute pancreatitis is associated with systemic inflammation and organ failure. Serum cystatin C and serum or urine NGAL have been shown to predict or diagnose AKI in AP; however, this evidence come from the single center studies of low number of patients. Other markers, such as urinary kidney injury molecule-1, cell cycle arrest biomarkers (tissue inhibitor metalloproteinase-2 and urine insulin-like growth factor-binding protein 7), interleukin-18, liver-type fatty acid-binding protein, or calprotectin have been studied in other populations suffering from systemic inflammatory states. In AP, the potential markers of AKI may be significantly influenced by either dehydration or inflammation, and the impact of these factors may be difficult to distinguish from kidney injury. The subject of AKI complicating AP is understudied. More studies are needed, for both exploratory (to choose the best markers) and clinical (to evaluate the diagnostic accuracy of the chosen markers in real clinical settings).

MON-300 EFFICACY AND SAFETY OF CANAGLIFLOZIN, A SODIUM GLUCOSE COTRANSPORTER 2 (SGLT2) INHIBITOR, IN DIABETIC KIDNEY DISEASE: A RANDOMIZED OPEN-LABEL PROSPECTIVE TRIAL

Sodium glucose cotransporter 2 (SGLT2) inhibitors are expected to have, renoprotective effects based on the possible mechanism that SGLT2 inhibitors reduce hyperfiltration by blocking proximal tubule sodium reabsorption and activating tubuloglomerular feedback (TGF) and may decrease inflammatory, fibrotic, and hyperplastic response of proximal tubular cells by blocking glucose reabsorption into proximal tubular cells. Although SGLT2 inhibition is associated with an acute reduction in estimated glomerular filtration rate (eGFR) by about 4-6 mL/min per 1.73m2, eGFR typically has a tendency to return to baseline and remains stable thereafter. Furthermore, a 30 to 40% reduction in albuminuria was found. However, the effects of SGLT2 inhibition are unclear with regard to other kidney related biomarkers, such as those associated with tubulointerstitial damage. In the present study, we aimed to examine precisely the renoprotective effects of the SGLT2 inhibitor canagliflozin by measuring albuminuria, tubulointerstitial biomarkers, eGFR, and other metabolic parameters in patients with diabetic kidney disease (DKD) who are treated with renin-angiotensin system (RAS) inhibitors. In this prospective, open-label, parallel-group study, Japanese diabetes patients were randomized to receive either oral canagliflozin (100 mg/day) or usual care (control group) for 52 weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) and RAS inhibitors for 8 weeks; these drugs were continued during the study. A total of 44 patients were randomly assigned to the canagliflozin group (n = 22) or the control group (n = 22). Endpoints included changes in urinary albumin-to-creatinine ratio (UACR), other urinary biomarkers, laboratory and vital parameters, and adverse events. Both groups included 22 patients in the analysis. Mean change in UACR was -221 g/gCr and 81 mg/gCr in the canagliflozin and control groups, respectively (P=0.004). Percent reduction in UACR was significantly greater in the canagliflozin group than in the control group (-49 ± 26% vs. 24 ± 47 %; P<0.0001). Urinary liver-type fatty acid binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG), and β2-microglobulin levels were also significantly decreased in the canagliflozin group, but not in the control group. Mean change in eGFR at the end of the study was 0.7 and -3.4 mL/min/1.73m2 in the canagliflozin and control group, respectively (P=0.024). A significant decrease in body mass index (BMI), systolic, diastolic blood pressure (BP), and mean arterial pressure was observed in the canagliflozin group. In addition, canagliflozin was associated with a significant increase in hemoglobin concentrations and hematocrit levels. Canagliflozin treatment leads to a reduction in albuminuria, urinary L-FABP, NAG, and β2-microglobulin levels in patients with DKD, regardless of simultaneous RAS inhibition. Furthermore, after 52 weeks, canagliflozin, in contrast to the control treatment, significantly reduced HbA1c and was associated with reductions in body weight, BPs, and liver transaminase levels in patients with DKD. The effect of canagliflozin on UACR appeared to be, in large part, beyond the effects on glycemic control. These findings suggest that canagliflozin may be an appropriate treatment option for patients with DKD.

SAT-299 CD38 INHIBITION DECREASE RENAL OXIDATIVE STRESS IN DIABETIC KIDNEY DISEASE BY RESTORING OF SIRT3 ACTIVATION.

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease worldwide. Aging is recognized as one of the risk factors for the development of end-stage renal failure due to chronic kidney disease including DKD. Therefore, investigation of aging-related mechanisms would be needed to discover a novel therapeutic target to treat DKD. Nicotinamide adenine dinucleotide (NAD) levels decrease during aging and are involved in age-related metabolic decline. Previous report demonstrated that expression and activity of the NADase CD38 increase with aging and that CD38 is required for the age-related NAD decline and mitochondrial dysfunction via a pathway mediated at least in part by regulation of sirt3 activity. We already discovered that the expression of CD38 was significantly increased in diabetic kidney and reduction in Sirt3 activity contributes to mitochondrial oxidative stress by decreasing the activation of anti-oxidative enzymes in the kidney of diabetic model rats. So, we investigated whether the inhibition of CD38 suppress mitochondrial oxidative stress through restoring of Sirt3 activity in diabetic rats and high glucose-incubated human renal tubular epithelial cells (HK2 cells). We used Male non-diabetic Zucker Lean (ZL) and type2 diabetes model rats, Zucker Diabetic Fatty rats (ZDFRs). CD38 inhibitor, apigenin or saline were prepared for oral gavage at 20mg/kg/day for 5 times by a week ,continued 4weeks and sacrificed at 28 weeks of age. In vitro study, HK2 cells were cultured in standard or high glucose condition and were treated for 48 hours with 10 μM apigenin or DMSO. At 28 weeks of age, compared to ZL, ZDFRs exhibited elevated HbA1c levels, heavier kidney weight, increased urinary albumin, liver type fatty acid binding protein (L-FABP), and 8-hydroxy-2’ -deoxyguanosine (8-OHdG), excretion, histological tubulo-interstitial fibrosis. In the immunostaining, increased CD38 positive cell in the kidney, particularly tubulo-interstitial area. Expression of mRNA and protein of CD38 were all significantly elevated in renal cortex. Administration of apigenin inhibited mRNA and protein expression of CD38, decreased albumin/L-FABP/8-OHdG excretion and ameliorated tubulo-interstitial fibrosis. Apigenin suppressed overexpression of CD38 in diabetic kidney and may ameliorated tubular cell damage. In addition, ZDFRs showed abnormal mitochondrial morphology, such as swelling and loss of cristae in primal tubular cell. In renal mitochondria, the NAD+/NADH ratio was reduced, and acetylation levels of mitochondrial antioxidant enzymes such as isocitrate dehydrogenase 2 (IDH2) and superoxide dismutase (SOD2), regulated by sirt3 were increased in ZDFRs. While apigenin restored abnormal mitochondrial morphology, increased NAD+/NADH ratio and reduced the acetylation of IDH2 and SOD2. Similarly, high glucose medium incubation in HK2 cell elevated CD38 levels associated with the reduction in NAD+/NADH ratio and increasing acetylation levels of SOD2 and IDH2. Administration of apigenin increased NAD+/NADH ratio, decreased SOD2 and IDH2 acetylation. Administration of the CD38 inhibitor, apigenin restored the NAD+/NADH ratio, decreased the levels of IDH2 and SOD2 acetylation and renal oxidative stress. Therefore, inhibition of CD38 may be a therapeutic target for the suppression of DKD.

Neutrophil Gelatinase-Associated Lipocalin Is Not Associated with Tacrolimus-Induced Acute Kidney Injury in Liver Transplant Patients Who Received Mycophenolate Mofetil with Delayed Introduction of Tacrolimus.

Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication. The urinary neutrophil gelatinase-associated lipocalin (NGAL) level has been linked to tacrolimus-induced AKI in patients starting tacrolimus treatment the morning after liver transplantation. Here we tested this association using a different immunosuppression protocol: Mycophenolate mofetil administration beginning on Postoperative Day 1 and tacrolimus administration beginning on Postoperative Day 2 or 3. Urine samples were collected from 26 living donor liver transplant recipients before (Postoperative Day 1) and after (Postoperative Day 7 or 14) tacrolimus administration. NGAL levels were measured via enzyme-linked immunosorbent assays, as were those of three additional urinary biomarkers for kidney diseases: Monocyte chemotactic protein-1 (MCP-1), liver-type fatty acid-binding protein (L-FABP), and human epididymis secretory protein 4 (HE4). HE4 levels after tacrolimus administration were significantly higher in patients who developed AKI (n = 6) than in those who did not (n = 20), whereas NGAL, MCP-1, and L-FABP levels did not differ significantly before or after tacrolimus administration. These findings indicate that NGAL may not be a universal biomarker of AKI in tacrolimus-treated liver transplant recipients. To reduce the likelihood of tacrolimus-induced AKI, our immunosuppression protocol is recommended.

Protein-based cardiogenic shock patient classifier.

Cardiogenic shock (CS) is associated with high short-term mortality and a precise CS risk stratification could guide interventions to improve patient outcome. Here, we developed a circulating protein-based score to predict short-term mortality risk among patients with CS. Mass spectrometry analysis of 2654 proteins was used for screening in the Barcelona discovery cohort (n = 48). Targeted quantitative proteomics analyses (n = 51 proteins) were used in the independent CardShock cohort (n = 97) to derive and cross-validate the protein classifier. The combination of four circulating proteins (Cardiogenic Shock 4 proteins-CS4P), discriminated patients with low and high 90-day risk of mortality. CS4P comprises the abundances of liver-type fatty acid-binding protein, beta-2-microglobulin, fructose-bisphosphate aldolase B, and SerpinG1. Within the CardShock cohort used for internal validation, the C-statistic was 0.78 for the CardShock risk score, 0.83 for the CS4P model, and 0.84 (P = 0.033 vs. CardShock risk score) for the combination of CardShock risk score with the CS4P model. The CardShock risk score with the CS4P model showed a marked benefit in patient reclassification, with a net reclassification improvement (NRI) of 0.49 (P = 0.020) compared with CardShock risk score. Similar reclassification metrics were observed in the IABP-SHOCK II risk score combined with CS4P (NRI =0.57; P = 0.032). The CS4P patient classification power was confirmed by enzyme-linked immunosorbent assay (ELISA). A new protein-based CS patient classifier, the CS4P, was developed for short-term mortality risk stratification. CS4P improved predictive metrics in combination with contemporary risk scores, which may guide clinicians in selecting patients for advanced therapies.

Biomarker Predictors of Adverse Acute Kidney Injury Outcomes in Critically Ill Patients: The Dublin Acute Biomarker Group Evaluation Study

Background: The Dublin Acute Biomarker Group Evaluation (DAMAGE) Study is a prospective 2-center observational study investigating the utility of urinary biomarker combinations for the diagnostic and prognostic assessment of acute kidney injury (AKI) in a heterogeneous adult intensive care unit (ICU) population. The objective of this study is to evaluate whether serial urinary biomarker measurements, in combination with a simple clinical model, could improve biomarker performance in the diagnostic prediction of severe AKI and clinical outcomes such as death and need for renal replacement therapy (RRT). Methods: Urine was collected daily from patients admitted to the ICU, for a total of 7 post-admission days. Urine biomarker concentrations (neutrophil gelatinase-associated lipocalin [NGAL], α-glutathione S-transferase [GST], π-GST, kidney injury molecule-1 [KIM-1], liver-type fatty acid-binding protein [L-FABP], Cystatin C, creatinine, and albumin) were measured. Urine biomarkers were combined with a clinical prediction of AKI model, to determine ability to predict AKI (any stage, within 2 days or 7 days of ICU admission), or a ­30-day composite clinical outcome (RRT – or death). Results: A total of 257 (38%) patients developed AKI within 7 days of ICU admission. Of those who developed AKI, 106 (41%) patients met stage 3 AKI within 7 days of ICU admission and 208 patients of the entire study cohort (31%) met the composite clinical endpoint of in-hospital mortality or RRT within 30 days of ICU admission. The addition of urinary NGAL/albumin to the clinical model modestly improved the prediction of AKI, in particular severe stage 3 AKI (area under the curve [AUC] of 0.9 from 0.87, p = 0.369) and the prediction of 30-day RRT or death (AUC 0.83 from 0.79, p = 0.139). Conclusion: A clinical model incorporating severity of illness, patient demographics, and chronic illness with currently available clinical biomarkers of renal function was strongly predictive of development of AKI and associated clinical outcomes in a heterogeneous adult ICU population. The addition of urinary NGAL/albumin to this simple clinical model improved the prediction of severe AKI, need for RRT and death, but not at a statistically or clinically significant level, when compared to the clinical model alone.

Utility of urinary liver-type fatty acid-binding protein as a predictor of renal dysfunction in Japanese patients with HIV receiving tenofovir disoproxil fumarate with low urinary \u03b22 microglobulin levels: a retrospective observational study

BackgroundTenofovir disoproxil fumarate (TDF) is known to reduce estimated glomerular filtration rate (eGFR). It is clinically important to identify patients at high risk for renal dysfunction as early as possible. Among the tubular markers, urinary β2 microglobulin (Uβ2MG) is a well-known biomarker of TDF-related tubulopathy. However, renal dysfunction has often been occurred in patients receiving TDF with low Uβ2MG levels. Recently, urinary liver-type fatty acid–binding protein (UL-FABP) was suggested to be predictor of the progression of renal dysfunction. Thus, we focused on UL-FABP in patients receiving TDF with low Uβ2MG levels.MethodsA retrospective, observational, single-center study, between January 2013 and December 2016, was conducted. Two renal end points (> 25% decrement in eGFR and > 20 mL/min/1.73 m2 decrement relative to the baseline) were assessed. To estimate the effect of UL-FABP on time to the first event, log-rank test was performed.ResultsA total of 24 Japanese outpatients with human immunodeficiency virus receiving TDF were enrolled. The outcome each occurred in two patients during the follow-up period. UL-FABP levels ≥4.0 μg/g creatinine was significantly associated with > 25% decrement and > 20 mL/min/1.73 m2 decrement (p = 0.006 and 0.001, respectively).ConclusionBased on our preliminary analysis, UL-FABP levels ≥4.0 μg/g creatinine predict renal dysfunction in patients receiving TDF with low Uβ2MG levels.

FABP1 controls hepatic transport and biotransformation of \u03949-THC

The increasing use of medical marijuana highlights the importance of developing a better understanding of cannabinoid metabolism. Phytocannabinoids, including ∆9-tetrahydrocannabinol (THC), are metabolized and inactivated by cytochrome P450 enzymes primarily within the liver. The lipophilic nature of cannabinoids necessitates mechanism(s) to facilitate their intracellular transport to metabolic enzymes. Here, we test the central hypothesis that liver-type fatty acid binding protein (FABP1) mediates phytocannabinoid transport and subsequent inactivation. Using X-ray crystallography, molecular modeling, and in vitro binding approaches we demonstrate that FABP1 accommodates one molecule of THC within its ligand binding pocket. Consistent with its role as a THC carrier, biotransformation of THC was reduced in primary hepatocytes obtained from FABP1-knockout (FABP1-KO) mice. Compared to their wild-type littermates, administration of THC to male and female FABP1-KO mice potentiated the physiological and behavioral effects of THC. The stark pharmacodynamic differences were confirmed upon pharmacokinetic analyses which revealed that FABP1-KO mice exhibit reduced rates of THC biotransformation. Collectively, these data position FABP1 as a hepatic THC transport protein and a critical mediator of cannabinoid inactivation. Since commonly used medications bind to FABP1 with comparable affinities to THC, our results further suggest that FABP1 could serve a previously unrecognized site of drug-drug interactions.

Astragaloside IV ameliorates high glucose-induced HK-2 cell apoptosis and oxidative stress by regulating the Nrf2/ARE signaling pathway.

Diabetic nephropathy (DN) has become the major cause of end-stage renal disease increasing the mortality risk of diabetes. Research has demonstrated that the oxidative damage and apoptosis of renal tubular cells is present during DN. Astragaloside IV (AS-IV) has been widely used for the treatment of many diseases, however, the role and mechanism by which AS-IV may ameliorate high glucose-induced apoptosis and oxidative stress of the human proximal tubular cell line HK-2 remains largely unknown. The present study investigated the effect of AS-IV on high glucose-induced apoptosis and oxidative stress in HK-2 cells. Cell viability, apoptosis and protein expression were detected by Trypan blue staining, Cell Counting Kit-8 assay, terminal deoxynucleotidyl transferase 2′-deoxyuridine-5′-triphosphate nick-end labelling, flow cytometry and western blot analyses. In addition, enzymatic activities, including superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT) and lipid peroxide (LPO), were measured with the corresponding detection kits. DCFH-DA assay and flow cytometry were performed to detect the production of reactive oxygen species (ROS). Western blot analysis and reverse transcription-quantitative polymerase chain reaction were conducted to evaluate protein and mRNA expressions of the nuclear factor erythroid 2 like 2 (Nrf2)/antioxidant response element (ARE) signaling pathway. The results demonstrated that AS-IV significantly enhanced HK-2 cell viability induced by high glucose in a dose-dependent manner. In addition, AS-IV notably inhibited HK-2 cell apoptosis stimulated by high glucose, which may be associated with inhibition of BCL2 associated X protein, Cleaved-caspase-3 and Cleaved-caspase-9, expression and the promotion of Bcl-2. AS-IV significantly increased the activities of antioxidant enzymes SOD, GSH-Px and CAT, and decreased the high-glucose-induced ROS production in HK-2 cells, in a dose-dependent manner. Finally, it was determined that AS-IV regulated the Nrf2/ARE signaling pathway and inhibited the expression of liver-type fatty acid binding protein. In conclusion, these findings may provide evidence that AS-IV has a potential role for the treatment of DN.

Serum Liver-Type Fatty Acid-Binding Protein Is a Possible Prognostic Factor in Human Chronic Liver Diseases From Chronic Hepatitis to Liver Cirrhosis and Hepatocellular Carcinoma.

Liver‐type fatty acid–binding protein (L‐FABP) is a key regulator of fatty acid metabolism, but serum L‐FABP levels are not well investigated in chronic liver diseases. We aimed to elucidate the prognostic ability of serum L‐FABP in human chronic liver diseases and compare it with the albumin‐bilirubin (ALBI) score. In 242 chronic liver disease patients, including chronic hepatitis (CH, n = 100), liver cirrhosis (LC, n = 142), and presence of hepatocellular carcinoma (HCC, n = 144), serum L‐FABP levels were correlated with liver function (P < 0.0001), increased in LC compared with CH (P < 0.01), and correlated to ALBI score (P < 0.0001). Serum L‐FABP levels were increased in the presence of HCC (P < 0.0001), correlating to des‐gamma‐carboxy prothrombin (P < 0.0001), alpha‐fetoprotein (P = 0.009), and Barcelona‐Clinic Liver Cancer stage. In the average follow‐up period of 1,054 days, serum L‐FABP levels were elevated (P < 0.0001) in patients who eventually died. The area under the curve (AUC) of serum L‐FABP (0.764) was higher than that of ALB (0.709), and the patients with serum L‐FABP ≤ 6.8 ng/mL had significantly longer rates of survival (P < 0.0001). Serum L‐FABP (hazard ratio [HR] 4.0; P < 0.001), HCC (HR 3.7; P = 0.001), ALBI score (HR 2.7; P < 0.001), and age (HR 1.0; P = 0.049) were independent predictors of survival. In the subgroup who maintained liver function, the AUC of serum L‐FABP (0.751) was higher than that of ALB (0.643). In this subgroup, serum L‐FABP (HR 4.4; P = 0.002) and HCC (HR 13.9; P < 0.001) were independent predictors of survival. Conclusion: Serum L‐FABP is a possible predictor of survival in chronic liver diseases from CH to LC and HCC, including any subgroup that maintains liver function.

Biomarkers of Drug-Induced Kidney Toxicity.

Blood urea nitrogen and serum creatinine are imperfect markers of kidney function because they are influenced by many renal and nonrenal factors independent of kidney function. A biomarker that is released directly into the blood or urine by the kidney in response to injury may be a better early marker of drug-induced kidney toxicity than blood urea nitrogen and serum creatinine. Urine albumin and urine protein, as well as urinary markers kidney injury molecule-1 (KIM-1), β2-microglobulin (B2M), cystatin C, clusterin, and trefoil factor-3 (TFF-3) have been accepted by the Food and Drug Administration and European Medicines Agency as highly sensitive and specific urinary biomarkers to monitor drug-induced kidney injury in preclinical studies and on a case-by-case basis in clinical trials. Other biomarkers of drug-induced kidney toxicity that have been detected in the urine of rodents or patients include IL-18, neutrophil gelatinase-associated lipocalin, netrin-1, liver-type fatty acid-binding protein (L-FABP), urinary exosomes, and TIMP2 (insulin-like growth factor-binding protein 7)/IGFBP7 (insulin-like growth factor-binding protein 7), also known as NephroCheck, the first Food and Drug Administration-approved biomarker testing platform to detect acute kidney injury in patients. In the future, a combined use of functional and damage markers may advance the field of biomarkers of drug-induced kidney toxicity. Earlier detection of drug-induced kidney toxicity with a kidney-specific biomarker may result in the avoidance of nephrotoxic agents in clinical studies and may allow for earlier intervention to repair damaged kidneys.

Acute kidney injury in cirrhosis: implications for liver transplantation.

Acute kidney injury (AKI) in cirrhosis consists of varying phenotypes, with hepatorenal syndrome (HRS) representing a single entity. Prompt recognition and diagnosis of AKI cause identifies appropriate therapeutic measures. This review provides an overview of AKI definitions, highlights challenges in quantifying renal impairment in cirrhosis, lists novel diagnostic AKI biomarkers, and summarizes transplantation implications. Biomarkers (neutrophil gelatinase-associated lipocalin, kidney injury molecule-1, interleukin-18, and liver-type fatty acid-binding protein) may assist in the identification of underlying acute tubular necrosis. Of these, neutrophil gelatinase-associated lipocalin is the most promising; however, significant overlap occurs among AKI phenotypes, with diagnostic values yet to be defined. Mainstay treatment of HRS consists of albumin and vasopressors. Acute-on-chronic liver failure grade independently predicts response to terlipressin treatment. Many end-stage liver disease patients with AKI have underlying chronic kidney disease with important implications on pre and postliver transplantation mortality. Simultaneous liver-kidney transplant candidacy is based on low likelihood of renal recovery. Novel biomarkers may assist in identification of acute tubular necrosis and persistent/severe AKI. Norepinephrine has been suggested to be inferior to terlipressin, with additional research required. Increasing acute-on-chronic liver failure grade correlates with lower likelihood of vasopressor response in HRS. Severe preliver transplantation AKI confers significantly worse postliver transplantation renal outcomes.

Clinical characteristics of autoimmune pancreatitis with IgG4 related kidney disease

PurposeTo clarify the clinical characteristics of autoimmune pancreatitis (AIP) in immunoglobulin (Ig)G4-related kidney disease (IgG4-RKD). Patients and methodsA total of 92 patients with AIP were divided into an IgG4-RKD-positive group (RKD-P group, n = 13) and an IgG4-RKD-negative group (RKD-N group, n = 79) on the basis of the diagnostic criteria for IgG4-RKD. Clinical characteristics, including: age; sex; the presence of extrapancreatic lesions other than renal lesions, proteinuria, and hematuria; serum concentrations of IgG, IgG4, IgE, and creatinine; and urinary concentrations of liver-type fatty acid binding protein, α1-microglobulin, β2-microglobulin, and N-acetyl-β-d-glucosaminidase were compared between the RKD-P and RKD-N groups. The clinical course of the RKD-P group was also characterized. ResultsThe prevalence of extrapancreatic lesions other than renal lesions was significantly higher in the RKD-P group (84.6% vs 43.0%,p < 0.01). Serum creatinine (1.19 mg/dl versus 0.74 mg/dl, p < 0.05), urinary β2-microglobulin (6609.8 μg/l vs 265.8 μg/l, p < 0.05), and the prevalence of proteinuria (30.7% vs 7.6%, p < 0.05) were significantly higher in the RKD-P group. Nine out of thirteen patients in the RKD-P group had multiple low-density renal lesions on enhanced computed tomography, 3 patients had multiple high-intensity lesions on diffusion-weighted magnetic resonance images, and 1 patient had diffuse thickening of the renal wall, with a smooth intra-luminal surface. ConclusionsPatients who had AIP with IgG4-RKD were more likely to have extrapancreatic lesions other than those in the kidney, and their serum creatinine and urinary β2-microglobulin concentrations were significantly higher than in those without IgG4-RKD.

P-NGAL Day 1 predicts early but not one year graft function following deceased donor kidney transplantation - The CONTEXT study.

BackgroundEarly markers to predict delayed kidney graft function (DGF) may support clinical management. We studied the ability of four biomarkers (neutrophil gelatinase associated lipocalin (NGAL), liver-type fatty acid-binding protein (L-FABP), cystatin C, and YKL-40) to predict DGF after deceased donor transplantation, and their association with early graft function and GFR at three and twelve months.Methods225 deceased donor kidney transplant recipients were included. Biomarkers were measured using automated assays or ELISA. We calculated their ability to predict the need for dialysis post-transplant and correlated with the estimated time to a 50% reduction in plasma creatinine (tCr50), measured glomerular filtration rate (mGFR) and estimated GFR (eGFR).ResultsAll biomarkers measured at Day 1, except urinary L-FABP, significantly correlated with tCr50 and mGFR at Day 5. Plasma NGAL at Day 1 and a timed urine output predicted DGF (AUC = 0.91 and AUC 0.98). Nil or only weak correlations were identified between early biomarker levels and mGFR or eGFR at three or twelve months.ConclusionHigh plasma NGAL at Day 1 predicts DGF and is associated with initial graft function, but may not prove better than P-creatinine or a timed urine output. Early biomarker levels do not correlate with one-year graft function.Trial registrationClinicalTrials.gov NCT01395719

Effects of the SGLT-2 Inhibitor Canagliflozin on Adenine-Induced Chronic Kidney Disease in Rats.

SGLT-2 inhibitors have been shown to be nephroprotective in diabetes. Here, we examined if one of these drugs (canagliflozin) could also ameliorate non-diabetic chronic kidney disease (CKD). CKD was induced in rats by feeding them adenine (0.25%w/w for 35 days) and canagliflozin (10 or 25 mg/kg, by gavage) was given with or without adenine. Several conventional and novel plasma and urine biomarkers and tissues morphology were used to investigate the canagliflozin effect on kidney structure and function. Rats fed adenine showed the typical features of CKD that included elevation of blood pressure, decreased food intake and growth, increased water intake and urine output, decrease in creatinine clearance, and increase in urinary albumin/creatinine ratio, liver-type fatty acid binding protein, N-acetyl-beta-D-glucosaminidase, and plasma urea, creatinine, uric acid, calcium, indoxyl sulfate and phosphorus concentrations. Adenine also increased concentrations of several biomarkers of inflammation such as neutrophil gelatinase-associated lipocalin, interleukin-6, tumor necrosis factor alpha, clusterin, cystatin C and interleukin-1β, and decreased some oxidative biomarkers in kidney homogenate, such as superoxide dismutase, catalase, glutathione reductase, total antioxidant activity, and also urinary 8-isoprostane and urinary 8-hydroxy-2-deoxy guanosine. Adenine significantly increased the renal protein content of Nrf2, caused renal tubular necrosis and fibrosis. Given alone, canagliflozin at the two doses used did not significantly alter any of the parameters mentioned above. When canagliflozin was given concomitantly with adenine, it significantly and dose - dependently ameliorated all the measured adenine - induced actions. Canagliflozin ameliorated adenine - induced CKD in rats, through reduction of several inflammatory and oxidative stress parameters, and other indices such as uremic toxins, and by antagonizing the increase in the renal content of the transcription factor Nrf2. The drug caused no overt or significant untoward effects, and its trial in patients with CKD may be warranted.

Disrupted tubular parathyroid hormone/parathyroid hormone receptor signaling and damaged tubular cell viability possibly trigger postsurgical kidney injury in patients with advanced hyperparathyroidism.

BackgroundParathyroidectomy (PTX) that alleviates clinical manifestations of advanced hyperparathyroidism, including hypercalcemia and hypophosphatemia, is considered the best protection from calcium overload in the kidney. However, little is known about the relationship between postsurgical robust parathyroid hormone (PTH) reduction and perisurgical renal tubular cell viability. Post-PTX kidney function is still a crucial issue for primary hyperparathyroidism (PHPT) and tertiary hyperparathyroidism after kidney transplantation (THPT).MethodsAs a clinical study, we examined data from 52 consecutive patients (45 with PHPT, 7 with THPT) who underwent PTX in our center between 2015 and 2017 to identify post-PTX kidney injury. Their clinical data, including urinary liver-type fatty acid-binding protein (L-FABP), a tubular biomarker for acute kidney injury (AKI), were obtained from patient charts. An absolute change in serum creatinine level of 0.3 mg/dL (26.5 µmol/L) on Day 2 after PTX defines AKI. Post-PTX calcium supplement dose adjustment was performed to strictly maintain serum calcium at the lower half of the normal range. To mimic post-PTX-related kidney status, a unique parathyroidectomized rat model was produced as follows: 13-week-old rats underwent thyroparathyroidectomy (TPTX) and/or 5/6 subtotal nephrectomy (NX). Indicated TPTX rats were given continuous infusion of a physiological level of 1-34 PTH using a subcutaneously implanted osmotic minipump. Immunofluorescence analyses were performed by polyclonal antibodies against PTH receptor (PTHR) and a possible key modulator of kidney injury, Klotho.ResultsPatients’ estimated glomerular filtration rate (eGFR) did not have any clinically relevant change (62.5 ± 22.0 versus 59.4 ± 21.9 mL/min/1.73 m2, NS), whereas serum calcium (2.7 ± 0.18 versus 2.2 ± 0.16 mmol/L, P < 0.0001) and phosphorus levels (0.87 ± 0.19 versus 1.1 ± 0.23 mmol/L, P < 0.0001) were normalized and PTH decreased robustly (181 ± 99.1 versus 23.7 ± 16.8 pg/mL, P < 0.0001) after successful PTX. However, six patients who met postsurgical AKI criteria had lower eGFR and greater L-FABP than those without AKI. Receiver operating characteristics (ROC) analysis revealed eGFR <35 mL/min/1.73 m2 had 83% accuracy. Strikingly, L-FABP >9.8 µg/g creatinine had 100% accuracy in predicting post-PTX-related AKI. Rat kidney PTHR expression was lower in TPTX. PTH infusion (+PTH) restored tubular PTHR expression in rats that underwent TPTX. Rats with TPTX, +PTH and 5/6 NX had decreased PTHR expression compared with those without 5/6 NX. 5/6 NX partially cancelled tubular PTHR upregulation driven by +PTH. Tubular Klotho was modestly expressed in normal rat kidneys, whereas enhanced patchy tubular expression was identified in 5/6 NX rat kidneys. This Klotho and expression and localization pattern was absolutely canceled in TPTX, suggesting that PTH indirectly modulated the Klotho expression pattern. TPTX +PTH recovered tubular Klotho expression and even triggered diffusely abundant Klotho expression. 5/6 NX decreased viable tubular cells and eventually downregulated tubular Klotho expression and localization.ConclusionsPreexisting tubular damage is a potential risk factor for AKI after PTX although, overall patients with hyperparathyroidism are expected to keep favorable kidney function after PTX. Patients with elevated tubular cell biomarker levels may suffer post-PTX kidney impairment even though calcium supplement is meticulously adjusted after PTX. Our unique experimental rat model suggests that blunted tubular PTH/PTHR signaling may damage tubular cell viability and deteriorate kidney function through a Klotho-linked pathway.

Temporal changes in urinary excretion of liver-type fatty acid binding protein (L-FABP) in acute kidney injury model of domestic cats: a preliminary study.

Liver-type fatty acid–binding protein (L-FABP) is a biomarker for the early detection of renal diseases in humans. It is secreted along with cytotoxic oxidation products from proximal tubular epithelial cells under conditions of ischemia and/or oxidative stress. This study examined urinary L-FABP excretion under renal ischemia in feline acute kidney injury (AKI) model. L-FABP excretion increased immediately after renal ischemia/reperfusion, despite the absence of obvious structural damage to the kidneys, in the two AKI model cats studied. L-FABP was detected in the renal tubular lumen immediately after renal ischemia/reperfusion in the two cats, but not in a sham surgery cat. These results suggested that high L-FABP excretion is a pathophysiological response associated with antioxidant defense in proximal tubules with renal ischemia and/or oxidative stress in a feline model.

Novel Biomarkers of Contrast-Induced Kidney Injury after Endovascular Procedures: An Interventional Cardiologists Notion

Modern achievements of interventional cardiology in treatment of coronary heart disease (CHD) have significantly increased frequency of interventions and volume of contrast media (CM). Contrast-induced acute kidney injury (CIAKI) associated with CM administration is determined by 26.5 μmol/l increase in serum creatinine (SCr) within 48 - 72 hours or > 1.5-fold SCr increase versus its known or estimated level in the previous 7 days. Without effective disease management, prevention with early CIAKI risk stratification and cessation of nephrotoxic medications taken by patients are important. Given significant complexity in existing CIAKI treatment, modern therapeutic options are limited only to adequate renal injury prevention. The problem’s significance and diagnostic limitations associated with SCr definition require search for clinically and diagnostically significant AKI biomarkers. In terms of coronarography and percutaneous coronary interventions, several studies have been conducted on clinical and diagnostic significance of some biomarkers. This article characterizes and discloses prospective practical use of neutrophil gelatinase-associated lipocalin (NGAL), liver-type fatty acid binding protein (L-FABP), kidney injury molecule-1 (KIM-1), cystatin C (CysC) and interleukins-6,8,18 (IL-6,8,18) in interventional cardiology.

Assessment of Urinary Liver-Type Fatty Acid Binding Protein (LFABP) Levels in Type 2 Diabetes Mellitus Patients with Nephropathy

Assessment of Urinary Liver-Type Fatty Acid Binding Protein (LFABP) Levels in Type 2 Diabetes Mellitus Patients with Nephropathy

The Possibility of Urinary Liver-Type Fatty Acid-Binding Protein as a Biomarker of Renal Hypoxia in Spontaneously Diabetic Torii Fatty Rats

Background: Renal hypoxia is an aggravating factor for tubulointerstitial damage, which is strongly associated with renal prognosis in diabetic kidney disease (DKD). Therefore, urinary markers that can detect renal hypoxia are useful for monitoring DKD. Objective: To determine the correlation between urinary liver-type fatty acid-binding protein (L-FABP) and renal hypoxia using a novel animal model of type 2 diabetes. Methods: Male spontaneously diabetic Torii (SDT) fatty rats (n = 6) were used as an animal model of type 2 diabetes. Age- and sex-matched Sprague-Dawley (SD) rats (n = 8) were used as controls. Body weight, systolic blood pressure, and blood glucose levels were measured at 8, 12, 16, and 24 weeks of age. Urine samples and serum and kidney tissues were collected at 24 weeks of age. Microvascular blood flow index (BFI) was measured using diffuse correlation spectroscopy before sampling both the serum and kidneys for the evaluation of renal microcirculation at the corticomedullary junction. Results: Obesity, hyperglycemia, and hypertension were observed in the SDT fatty rats. Focal glomerular sclerosis, moderate interstitial inflammation, and fibrosis were significantly more frequent in SDT fatty rats than in SD rats. While the frequency of peritubular endothelial cells and phosphoendothelial nitric oxide synthase levels were similar in both types of rats, the degree of renal hypoxia-inducible factor-1α (HIF-1α) expression was significantly higher (and with no change in renal vascular endothelial growth factor expression levels) in the SDT fatty rats. Urinary L-FABP levels were significantly higher and renal microvascular BFI was significantly lower in the SDT fatty rats than in the SD rats. Urinary L-FABP levels exhibited a significant positive correlation with renal HIF-1α expression and a significant negative correlation with renal microvascular BFI. Conclusions: Urinary L-FABP levels reflect the degree of renal hypoxia in DKD in a type 2 diabetic animal model. Urinary L-FABP may thus prove useful as a renal hypoxia marker for monitoring DKD in patients with type 2 diabetes in clinical practice.