Biomarkers Of Acute Kidney Injury Research Articles

Smartphone surface plasmon resonance imaging for the simultaneous and sensitive detection of acute kidney injury biomarkers with noninvasive urinalysis.

A surface plasmon resonance imaging (SPRi) platform integrated with a smartphone was constructed for the simultaneous and sensitive detection of acute kidney injury (AKI) biomarkers. The smartphone SPRi platform was developed without the requirement of additional light and power sources. The LED flash of the smartphone was used as the light source for the excitation of surface plasmon resonance of a gold sensor chip based on the Kretschmann configuration, while the reflected light was collected by the camera of the smartphone. This smartphone SPRi system was conveniently fabricated by 3D printing and showed a sensitivity of 1.78 × 10-5 refractive index unit (RIU). In addition, based on a magnetic nanoparticle-enhanced sandwich immunoassay, the smartphone SPRi system with a gold array chip was employed for the detection of multiple AKI biomarkers, with a low limit of detection (LOD) of 0.19 ng ml-1, 0.51 ng ml-1 and 0.7 ng ml-1 for the simultaneous detection of neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18) and retinol-binding protein (RBP) in urine, respectively. The biosensors demonstrated high specificity and sensitivity for the simultaneous detection of multiple AKI biomarkers in PBST and urine. The smartphone SPRi system provided a portable and cost-effective platform for point-of-care diagnosis, in-field healthcare and environmental monitoring.

Clinical Implementation of NGAL Testing to Improve Diagnostic Assessment of AKI Episodes in a Canadian Center.

Background:The differential diagnosis of acute kidney injury (AKI) episodes is often challenging. Novel AKI biomarkers have shown their utility to improve prognostic prediction and diagnostic assessment in various research populations but their implementation in standard clinical practice is still rarely reported.Objective:To report the differential diagnostic ability and associated clinical utility of the neutrophil gelatinase-associated lipocalin (NGAL) testing in a real-life setting of a heterogeneous AKI population.Design:This is a retrospective cohort study combined with a clinical audit using questionnaires distributed to consultant nephrologists following NGAL results.Setting:The first 250 consecutive patients with a confirmed AKI where an NGAL test (plasma NGAL [pNGAL] or urine NGAL [uNGAL]) was ordered from a large academic center in Montreal, Canada from January 2021 to August 2021.Patients:Patients were classified into 3 groups based on the final AKI etiology category (functional, intrarenal, and postrenal) following definitive adjudication by 2 independent nephrologists.Methods:The ability of plasma NGAL (pNGAL), urine NGAL (uNGAL), and uNGAL-to-creatinine ratio (uNGAL/Cr) to discriminate intrarenal from functional AKI etiologies was compared to standard urine chemistry (FENa) and proteinuria. A logistic regression was used to evaluate the association between intrarenal AKI and increased biomarker levels. The overall clinical utility and appreciation of the NGAL test was evaluated using a questionnaire completed prospectively by the consultant nephrologist at the time of receiving the NGAL result. The NGAL results were prospectively available to clinicians with a median time of 2.9 (1.3-7.4) hours from the initial order.Results:A total of 214 uNGAL and 44 pNGAL were ordered from 100 functional, 139 intrarenal and 11 postrenal AKI episodes after final adjudication. The discriminative ability of FENa (AUC 0.68 [95% CI: 0.61-0.75]) was lower than uNGAL (AUC 0.80 [95% CI: 0.73-0.86]) and uNGAL/Cr (AUC 0.83 [95% CI: 0.77-0.88]) but better than pNGAL (AUC 0.66 [95% CI: 0.48-0.85]). According to consultant nephrologists, the NGAL testing has led to a change in clinical management in 42% of cases.Limitations:Data reported came from a single center and NGAL was reserved for more complex cases, which limits generalizability. No biopsy has been performed for most AKI cases as the final adjudication was based on a retrospective review of the hospitalization episode.Conclusions:Neutrophil gelatinase-associated lipocalin testing can be successfully integrated as part of the diagnostic workup for AKI in clinical practice. The integration of tubular damage biomarkers to functional biomarkers can further improve the differential diagnostic assessment. However, the impact of such biomarkers on AKI management and associated outcomes still needs further validation.

Preclinical Evaluation of the Renal Toxicity of Oligonucleotide Therapeutics in Mice.

Antisense oligonucleotides (ASO) therapeutics hold great promise for the treatment of numerous diseases, and several ASO drugs have now reached market approval, confirming the potential of this approach. However, some candidates have also failed, due to limited biodistribution/uptake and poor safety profile. In pursuit of better delivery and higher cellular uptake, ASO are being optimized, and new chemistries are developed or conjugated with various ligands. While these developments may lead to candidates with higher potency, it is important to keep the safety aspects in sight and screen for potential toxicity in early phases of preclinical development to avoid subsequent failure in clinical development. Our understanding of ASO-mediated toxicity keeps improving with increased preclinical and clinical data available. In this chapter, we will focus on the assessment of renal toxicity in mice and describe methods to measure the levels of general urinary biomarkers as well as acute kidney injury biomarkers following ASO treatment.

Subclinical AKI and Clinical Outcomes in Elderly Patients Undergoing Cardiac Surgery: Diagnostic Utility of NGAL versus Standard Creatinine Increase Criteria

Background: Acute kidney injury (AKI) is a common and serious postoperative complication in patients undergoing cardiac surgery and its incidence is particularly high among elderly patients. Cardiac surgery-associated AKI (CSA-AKI) represents the second most common cause of AKI in the intensive care unit but its true incidence could be underestimated, especially in elderly population. The current biomarkers of AKI are unreliable and delayed during acute changes in kidney function. In the setting of subclinical AKI (SAKI), biomarkers of tubular damage, such as NGAL, seem to be an early indicator of kidney damage. The aim of this study was to investigate NGAL utility in the SAKI diagnosis in the first 48 h after cardiac surgery and its helpfulness in predicting adverse clinical outcomes in comparison to current criteria for AKI. Methods: This is an observational study of 72 patients admitted to San Bortolo’s cardiac surgery department for elective cardiosurgical procedure enrolled over a 5-months period. All patients underwent peripheral venous sample 48 h after cardiac surgery to assess plasmatic creatinine (48Cr) and NGAL (48pNGAL) in addition to exams already foreseen by clinical practice. For each patient we studied renal, respiratory and cardiovascular outcome during hospitalization as well as 30 days and 6 months mortality. Creatinine Increase AKI (CrIAKI) was defined by 48CrI ≥0.3 mg/dL and SAKI was defined by 48pNGAL ≥100 pg/dL. We also assessed Respiratory (ArespO) as well as Cardiovascular (ACvO) outcome. Results: Thirty days mortality was 8.3% (6 patients) and 6 months mortality was 12.5% (9 patients). A total of 27 patients (37.5%) presented AKI according to KDIGO (4) and 4 (5.5%) needed renal replacement therapy (RRT). SAKI was significantly associated with 30 days mortality (p = 0.0238), 6 months mortality (p = 0.002), Adverse renal outcome (ARenO) (p = 0.004) and need for RRT (p = 0.005). CrIAKI was significantly associated with 30 days mortality (p = 0.009) and ARenO (p = 0.0001), but not with 6 months mortality nor need for RRT.

Assessment of the diagnostic ability of RIFLE classification and neutrophil gelatinase-associated lipocalin biomarker in detecting acute kidney injury in newborns at the intensive care unit

Introduction/Objective. This study was designed to demonstrate the association of the RIFLE classification and neutrophil gelatinase-associated lipocalin (NGAL) in predicting of newborns with acute kidney injury (AKI). Methods. This was a prospective study. We included 100 newborns suspected of having a kidney injury. These newborns were admitted to the intensive care unit (ICU) at the University Clinic of Pediatrics from the period of two years. The severity of the disease was determined by RIFLE classification. The biochemical marker NGAL was included in this study because it is an early biomarker of AKI in newborns. The statistical processing of the material was by methods of descriptive statistics. Results. The prevalence rate of AKI was 6.25%, but according to the RIFLE classification the prevalence was 8.7%. According to RIFLE classification, we reported ?risk? in 36%, ?injury? in 50% and ?failure? in 14% of newborns with AKI. In newborns with perinatal asphyxia, kidney injury was seen in 34% and 30%, making perinatal asphyxia the most common predisposing factor. The difference in average value of the score for neonatal acute physiology with perinatal extension in newborns with AKI and the control group without AKI was confirmed significant (p < 0.001). Also, there was a significant difference (p < 0.001) between serum creatinine and urinary NGAL values, on the day they were admitted to the ICU. Conclusion. In newborns hospitalized in the ICU, AKI is a serious condition. We could identify kidney injury and follow up the progression of the disease by using RIFLE classification. The need for early diagnosis of kidney injury, in a period when the disease is not clinically manifest, in the first hours of its occurrence, is provided by NGAL.

Smartphone Surface Plasmon Resonance Imaging for the Simultaneous and Sensitive Detection of Acute Kidney Injury Biomarkers with Noninvasive Urinalysis

Smartphone Surface Plasmon Resonance Imaging for the Simultaneous and Sensitive Detection of Acute Kidney Injury Biomarkers with Noninvasive Urinalysis

Immunomodulatory response and serum level of neutrophil gelatinase associated lipocalin (NGAL) as a marker of acute kidney injury in wistar rats exposed to pyrethroids

BACKGROUND: Insecticide usage has increased in the tropics and subtropics due to the high prevalence of vector-borne infections, even though insecticide use effectively reduces insect-borne diseases. Insecticide exposure can cause oxidative stress and have severe consequences for human health. The study was then designed to evaluate oxidative stress and its effects on immunomodulatory and renal integrity among Wistar rats exposed to pyrethroids. METHODS: Eighty-four Wistar rats were randomly selected and divided into two groups. Fifty-one rats were exposed to 1.2 %w/v pyrethroids, while the remaining thirty-three rats were grouped as non-exposed. The groups were divided into three different groups, each with 7, 21, and 41 days. After days of exposure, the animals in each group were anesthetized, and blood samples were collected from the inferior vena cava. Using standard spectrophotometric techniques, the levels of total antioxidant status (TAS), malondialdehyde (MDA), glutathione (GSH), hydrogen peroxide (H2O2), urea, creatinine and uric acid were determined. Blood activities of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT) were determined. ELISA was used to determine levels of IgG, IgA, IgE, TNF-α, and NGAL. Data obtained were statistically compared. RESULTS: The serum mean levels of SOD, GPx, CAT, GSH, and TAS were significantly reduced (p < 0.05) while mean levels of MDA, H2O2, IgG, IgE, IgA, TNFα, neutrophil gelatinase-associated lipocalin (NGAL), urea, uric acid, and creatinine were significantly elevated (p < 0.05) from 7 to 41 days exposure in exposed groups. NGAL had a higher area under the ROC curve than urea and creatinine. CONCLUSIONS: This study observed that pyrethroids can cause oxidative stress, deplete antioxidant levels, nephrotoxicity, and may modulate both humoral and cellular immune functions. It also established NGAL as a sensitive diagnostic tool and early biomarker for acute kidney injury (AKI).

Acute Kidney Injury in Cardiac Surgery with Cardiopulmonary Bypass

Changes in classification criteria and active introduction of biomarkers of acute kidney injury (KDIGO, 2012) are changing approaches to diagnosis and treatment of postoperative renal dysfunction including cardiac surgery patients operated with cardiopulmonary bypass (CPB). The objective: to compare the detection rate of AKI after surgery with CPB with the use of biomarkers and kidney disease improving global outcomes criteria, as well as to evaluate the cause and localization of structural changes of the nephron.Subjects and Methods. A monocenter observational study among elective cardiac surgery patients (n = 97) was conducted. Inclusion criteria: age over 18 years, duration of surgery (coronary bypass surgery, prosthetic heart valves) from 90 to 180 minutes, no signs of end stage kidney disease. AKI was diagnosed based on changes in serum creatinine and biomarkers (NGAL, IgG, albumin in urine). The studied parameters were recorded 15 minutes after the start and end of anesthesia, as well as 24 and 48 hours after surgery. Retrospectively, the group was divided into three subgroups: 1) patients without AKI after surgery; 2) patients in whom signs of AKI were detected after 24 hours but regressed by the 48th hour; 3) patients in whom AKI persisted during all 48 hours of follow-up.Results. 24 hours after surgery, AKI based on KDIGO criteria was recorded in 56.3% of patients. Using biomarkers, signs of tubular damage (NGAL) at the end of anesthesia were detected in 95.9% of patients; after 24 hours, they were registered in 73.2% of cases. In a subgroup where AKI persisted for more than 24 hours, glomeruli were damaged in addition to tubules which was manifested not only by selective but also by non-selective proteinuria. The duration of CPB, hemodilution (Hb < 90 g/l), the release of free hemoglobin in the blood (> 1.5 mg/l) at low (< 1 g/l) values of haptoglobin were significantly associated with AKI development.Conclusion. The KDIGO criteria do not allow detecting a subclinical form of renal dysfunction which may occur in about 40% of patients after surgery with CPB. AKI can be caused by damage to both the tubular part of the nephron and glomeruli in cases of prolonged CPB with the development of hemolysis, the release of free hemoglobin in the blood, and persisting anemia at the end of the surgery. The NGAL assessment makes it possible to detect subclinical kidney injury in the absence of elevated serum creatinine levels.

Advances in Biosensor Technologies for Acute Kidney Injury.

Acute kidney injury (AKI) is one of the most prevalent and complex clinical syndromes with high morbidity and mortality. The traditional diagnosis parameters are insufficient regarding specificity and sensitivity, and therefore, novel biomarkers and their facile and rapid applications are being sought to improve the diagnostic procedures. The biosensors, which are employed on the basis of electrochemistry, plasmonics, molecular probes, and nanoparticles, are the prominent ways of developing point-of-care devices, along with the mutual integration of efficient surface chemistry strategies. In this manner, biosensing platforms hold pivotal significance in detecting and quantifying novel AKI biomarkers to improve diagnostic interventions, potentially accelerating clinical management to control the injury in a timely manner. In this review, novel diagnostic platforms and their manufacturing processes are presented comprehensively. Furthermore, strategies to boost their effectiveness are also indicated with several applications. To maximize these efforts, we also review various biosensing approaches with a number of biorecognition elements (e.g., antibodies, aptamers, and molecular imprinting molecules), as well as benchmark their features such as robustness, stability, and specificity of these platforms.

Soluble FcγRIA expressed on monocytes (sCD64): A new serum biomarker of acute kidney injury in patients with suspected infection at emergency department admission.

Soluble FcγRIA expressed on monocytes (sCD64): A new serum biomarker of acute kidney injury in patients with suspected infection at emergency department admission.

The Higher Level of Neutrophil – Lymphocyte Ratio (NLR) and Serum Syndecan-1 Based on Timeline (First, Sixth, and Twenty-Fourth Hour) in Sepsis-Induced Acute Kidney Injury

This study aims to analyze the difference between the NLR and serum syndecan-1 level at the first,sixth, and twenty-fourth hours with the incidence of acute kidney injury (AKI) and non-AKI in sepsis.We observed thirty-one adult sepsis patients who admitted to the emergency room and ICU of Dr.Soetomo General Academic Hospital, Surabaya, Indonesia from March 30, 2020, to July 5, 2020 (fourmonth),and differentiated into two groups, AKI group (n=14) and non-AKI group (n=17). All septicpatients have been given the standard treatment based on Survival Sepsis Campaign 2018. The resultsshowed that the NLR at 1st-hours, 6th-hours, and 24th-hours in the non-AKI group were lower thanthose in the AKI group (1st: 15.9±2.6 vs 33.0±11.3; 6th: 14.2±1.8 vs 19.3±3.8; and 24th: 11.6±1.3 vs19.9±3.8) (p <0.00). Almost NLR at every groups based on serial hours were decreasing, except in theAKI group, the NLR at the 24th-hour group was higher than the NLR at 6-hour group, but still lowerthan the NLR at 1st-hours. Serum syndecan-1 levels were lower in the non-AKI group than in theAKI group, at 1st, 6th, and 24th-hours, (1st: 532.5±72.0 ng/mL vs 597.2±85.8 ng/mL; 6th: 557.6±71.6ng/mL vs 612.0±73.9 ng/mL; and 24th: 548.4±76.6 ng/mL vs 586.4±84.6 ng/mL) (p <0.05). It canbe concluded that the neutrophil-lymphocyte ratio (NLR) and serum syndecan-1 levels at 1st, 6th,and 24th hours is higher in the AKI compared to non-AKI groups in sepsis. Hence, NLR and serumsyndecan-1 have a potential biomarkers for sepsis-induced AKI.

Gestational age, sex, and time affect urine biomarker concentrations in extremely low gestational age neonates.

Background:Our understanding of the normative concentrations of urine biomarkers in premature neonates is limited.Methods:We evaluated urine from 750 extremely low gestational age neonates (ELGANs) without severe acute kidney injury (AKI) to determine how gestational age (GA) affects 10 different urine biomarkers at birth and over the first 30 postnatal days. Then we investigated if the urine biomarkers changed over time at 27, 30, and 34 weeks postmenstrual age (PMA). Next, we evaluated the impact of sex on urine biomarker concentrations at birth and over time. Finally, we evaluated if urine biomarkers were impacted by treatment with erythropoietin (Epo).Results:We found that all 10 biomarker concentrations differ at birth by GA and that some urine biomarker concentrations increase while others decrease over time. At 27 weeks PMA, 7/10 urine biomarkers differed by GA. By 30 weeks PMA, 5/10 differed and by 34 weeks PMA only osteopontin differed by GA. About half of the biomarker concentrations differed by sex, and 4/10 showed different rates of change over time between males vs. females. We found no differences in urine biomarkers by treatment group.Conclusions:The temporal, GA and sex differences need to be considered in urine AKI biomarker analyses.

The association of rs187238, rs19465518 and rs1946519 IL-8 polymorphisms with acute kidney injury in preterm infants.

BackgroundInterleukin 18 (IL-18) promoter polymorphisms (−656G > T, −607C > A, and −137G > C) affect serum IL- 18 (sIL-18) levels and are associated with renal injury.PurposeThis study aimed to determine the diagnostic utility of sIL-18 and urine IL-18 (uIL-18) as biomarkers for acute kidney injury (AKI) and analyse the association of IL-18 polymorphisms to AKI in preterm infants.MethodsBlood and urine samples were collected from 56 preterm infants with AKI and 56 without AKI to measure serum creatinine (SCr), sIL-18, and uIL-18. Genotyping of polymorphisms was performed and analysed, with AUC-ROCs analysis used to evaluate the diagnostic utility of s-/uIL-18 levels.ResultsThe median sIL-18 and uIL-18 levels were significantly higher than those without AKI. For a cutoff of >132 pg/mL, the sIL-18 expression had sensitivity and specificity of 80.36% and 60.71%, respectively, while for uIL-18, a cutoff of >900.7 pg/mL had sensitivity and specificity of 51.79% and 78.57%, respectively. The odds ratio of sIL-18 and uIL-18 to predict AKI in preterm infants was 5.89 (95%CI:2.31–15.02) and 4.15 (95%CI:1.58–10.89), respectively. The polymorphisms −137G > C and −656G > T were significantly associated with sIL-18 expression.ConclusionSerum and urine IL-18 levels are risk factors for and a moderate predictor of AKI in preterm infants.

Serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) Could Provide Better Accuracy Than Creatinine in Predicting Acute Kidney Injury Development in Critically Ill Patients.

Acute kidney injury (AKI) is one of the most common complications in critically ill patients. In recent years, studies have focused on exploring new biomarkers for the early diagnosis and prognosis of AKI. The aim of this study was to investigate serum prognostic biomarkers (neutrophil gelatinase-associated lipocalin, NGAL, and creatinine) of AKI in critically ill patients. The study included 266 critically ill, initially nonseptic, patients admitted to a multidisciplinary ICU. Serum levels of NGAL and creatinine were measured at ICU admission. ROC curves were generated to estimate the prognostic value of the biomarkers, while a logistic regression analysis was performed to assess their association with an increased AKI risk. Patients were divided in two groups based on the development (n = 98) or not (n = 168) of AKI during their ICU stay. Serum NGAL levels at ICU admission were significantly higher in those who subsequently developed AKI compared to those who did not (p < 0.0001). NGAL was shown to be more accurate in predicting AKI development than creatinine; furthermore, NGAL levels were associated with an increased risk of AKI development (1.005 (1.002–1.008), p < 0.0001). In the present study, we were able to demonstrate that increased serum NGAL levels at ICU admission might be predictive of AKI development during ICU hospitalization. Further studies are needed to support NGAL as a prognostic marker of acute kidney injury.

Abstract 12488: Serum Cystatin C is an Early Predictor of Acute Renal Injury in Infants After Cardiac Surgery With Cardiopulmonary Bypass

Introduction: Acute kidney injury (AKI) following infant cardiac surgery is common, with increased morbidity and mortality. Changes in urine output and/or serum creatinine (SCr) are unreliable in the detection of AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guidelines, and lag behind onset of renal injury. Serum Cystatin C (SCC) has been used as a biomarker of AKI in adults and older children. If SCC predicts AKI in infants following cardiopulmonary bypass (CPB) is unknown. Hypothesis: SCC is an early biomarker of AKI following infant cardiac surgery requiring CPB. Methods: 42 infants (&lt; 1 year of age) were prospectively enrolled when presenting for cardiac surgery requiring CPB. SCC and SCr were measured at baseline (pre-operatively), and at 12, 24, and 48 hours following CPB initiation, and changes in SCC and SCr compared to baseline (ΔSCC and ΔSCr, respectively) were calculated. AKI was defined using KDIGO guidelines, as an increase in SCr ≥ 50% and/or a urine output &lt; 0.5mL/kg/hr for ≥ 6-12 consecutive hours in the first 3 post-operative days. Subjects were divided in 2 groups: AKI and non-AKI. Receiver Operating Characteristic (ROC) curves were utilized to predict AKI based on ΔSCC and ΔSCr, and the area under the curve (AUC) was quantified. Results: AKI occurred in 17 (40.4%) subjects. Baseline SCC and SCr measurements were similar between groups, as were age, gender, weight, and CPB time. Post-operative SCC values decreased from baseline, suggesting volume overload. While SCC concentrations did not differ significantly between the 2 groups, ΔSCC measurements were significantly different in those with AKI at 12 hours (0.2 ± 0.3 vs 0.4 ± 0.2; p &lt; 0.01) and remained different at 24 hours (0.1 ± 0.3 vs 0.3 ± 0.2; p = 0.02). ΔSCr measurements were significantly greater in the AKI group at 24 hours (0.1 ± 0.1 vs 0.0 ± 0.1; p &lt; 0.01) and 48 hours (0.1 ± 0.1 vs. 0.0 ± 0.1; p &lt; 0.01) but not at 12 hours. ROC curves demonstrated that both the ΔSCC at 12 hours (AUC = 0.72; p = 0.02) and the ΔSCr at 24 hours (AUC= 0.78; p &lt; 0.01) predicted AKI. Conclusions: The 12 hour ΔSCC predicts AKI in infants after cardiac surgery, and correlated with a rise in ΔSCr the following day. Earlier detection of AKI would allow earlier post-operative intervention to mitigate renal injury in infants.

Abstract 10460: Urinary Fatty Acid Binding Protein 1 is a Biomarker for Impaired Proximal Tubular Protein Reabsorption and is Synergistically Enhanced by Concurrent Liver Injury

Introduction: Urinary fatty acid binding protein 1 (FABP1, also known as liver-type FABP) has been implicated as a biomarker of acute kidney injury (AKI) in humans. However, the precise biological mechanisms underlying its elevation remain elusive. Here, we show that urinary FABP1 primarily reflects impaired protein reabsorption in proximal tubule epithelial cells (PTECs). Methods and Results: Bilateral nephrectomy resulted in a marked increase in serum FABP1 levels, suggesting that the kidney is an essential organ for removing serum FABP1. Injected recombinant FABP1 was filtered through the glomeruli and robustly reabsorbed via the apical membrane of PTECs. Urinary FABP1 was significantly elevated in mice devoid of megalin, a giant endocytic receptor for protein reabsorption. Elevation of urinary FABP1 was also observed in patients with Dent disease, a rare genetic disease characterized by defective megalin function in PTECs. Urinary FABP1 levels were exponentially increased following acetaminophen overdose, with both nephrotoxicity and hepatotoxicity observed. FABP1-deficient mice with liver-specific overexpression of FABP1 showed a massive increase in urinary FABP1 levels upon acetaminophen injection, indicating that urinary FABP1 is liver-derived. Lastly, we employed transgenic mice expressing diphtheria toxin receptor (DT-R) either in a hepatocyte- or PTEC-specific manner, or both. Upon diphtheria toxin (DT) administration, massive excretion of urinary FABP1 was induced in mice with both kidney and liver injury, while mice with either injury type showed marginal excretion. Conclusions: Collectively, our data demonstrated that intact PTECs have a considerable capacity to reabsorb liver-derived FABP1 through a megalin-mediated mechanism. Thus, urinary FABP1, which is synergistically enhanced by concurrent liver injury, is a biomarker for impaired protein reabsorption in AKI. These findings address the use of urinary FABP1 as a biomarker of histologically injured PTECs that secrete FABP1 into primary urine, and suggest the use of this biomarker to simultaneously monitor impaired tubular reabsorption and liver function.

Intra-operative and early post-operative prediction of cardiac surgery-associated acute kidney injury: Urinary oxygen tension compared with plasma and urinary biomarkers.

Acute kidney injury (AKI) is a common and serious post-operative complication of cardiac surgery. The value of a predictive biomarker is determined not only by its predictive efficacy, but also by how early this prediction can be made. For a biomarker of cardiac surgery-associated AKI, this is ideally during the intra-operative period. Therefore, in 82 adult patients undergoing cardiac surgery requiring cardiopulmonary bypass (CPB), we prospectively compared the predictive efficacy of various blood and urinary biomarkers with that of continuous measurement of urinary oxygen tension (UPO2 ) at pre-determined intra- and post-operative time-points. None of the blood or urine biomarkers we studied showed predictive efficacy for post-operative AKI when measured intra-operatively. When treated as a binary variable (≤ or > median for the whole cohort), the earliest excess risk of AKI was predicted by an increase in urinary neutrophil gelatinase-associated lipocalin (NGAL) at 3h after entry into the intensive care unit (odds ratio [95% confidence limits], 2.86 [1.14-7.21], p=0.03). Corresponding time-points were 6h for serum creatinine (3.59 [1.40-9.20], p=0.008), and 24h for plasma NGAL (4.54 [1.73-11.90], p=0.002) and serum cystatin C (6.38 [2.35-17.27], p=0.001). In contrast, indices of intra-operative urinary hypoxia predicted AKI after weaning from CPB, and in the case of a fall in UPO2 to ≤10mmHg, during the rewarming phase of CPB (3.00 [1.19-7.56], p=0.02). We conclude that continuous measurement of UPO2 predicts AKI earlier than plasma or urinary NGAL, serum cystatin C, or early post-operative changes in serum creatinine.

Prospective evaluation of 5 urinary biomarkers as predictors of acute kidney injury in nonazotemic, hospitalized dogs.

BackgroundEarly recognition of acute kidney injury (AKI) is hindered by current definitions and use of traditional, insensitive markers.Hypothesis/ObjectivesUrinary (u) activity of γ‐glutamyl transpeptidase (GGT) and alkaline phosphatase (ALP), and concentrations of heat‐shock protein 70 (HSP70) and interleukins (ILs) ‐6 and ‐18, are predictive biomarkers for AKI and survival.AnimalsNonazotemic, hospitalized dogs (n = 118) and healthy controls (n = 20).MethodsA prospective observational study. Nonazotemic dogs at risk of AKI were recruited and their urinary biomarker concentrations were measured at presentation. Serum creatinine (sCr) and symmetric dimethylarginine (sSDMA) were measured daily until discharge/death.ResultsThe overall case fatality rate was 18.6%. Fifteen dogs (12.7%) developed AKI, which was associated with death (relative risk, 3.2; 95% confidence interval [CI], 1.57‐6.55). All 5 urinary biomarkers were significantly higher in hospitalized dogs compared to controls, with minimal overlap. uHSP70/uCr, uGGT/uCr, and uIL‐6/uCr at presentation were higher in dogs which later developed AKI. Areas under the receiver operator characteristic curve (AUROC) (95% CI) for the 3 biomarkers as predictors of AKI were 0.67 (0.51‐0.83), 0.68 (0.55‐0.81), and 0.78 (0.65‐0.91), respectively. When they were categorically classified as elevated/normal, each additional elevated biomarker increased the odds for AKI (OR, 2.83; 95% CI, 1.23‐6.52, P = .01). Agreement between sCr and sSDMA was poor (Cohen's kappa = .071). The AUROC of SDMA at presentation for AKI prediction was 0.73 (0.51‐0.95).Conclusions and Clinical ImportanceKidney injury was common, irrespective of subsequent worsening of azotemia or death. The predictive value of individual urinary biomarkers was reduced by moderate sensitivities and specificities. SDMA showed moderate discriminatory utility for AKI prediction, and often displayed discordant results with sCr.

In Vivo and In Vitro Evaluation of Urinary Biomarkers in Ischemia/Reperfusion-Induced Kidney Injury.

Oxidative stress plays an important role in the pathophysiology of acute kidney injury (AKI). Previously, we reported that vanin-1, which is involved in oxidative stress, is associated with renal tubular injury. This study was aimed to determine whether urinary vanin-1 is a biomarker for the early diagnosis of AKI in two experimental models: in vivo and in vitro. In a rat model of AKI, ischemic AKI was induced in uninephrectomized rats by clamping the left renal artery for 45 min and then reperfusing the kidney. On Day 1 after renal ischemia/reperfusion (I/R), serum creatinine (SCr) in I/R rats was higher than in sham-operated rats, but this did not reach significance. Urinary N-acetyl-β-D-glucosaminidase (NAG) exhibited a significant increase but decreased on Day 2 in I/R rats. In contrast, urinary vanin-1 significantly increased on Day 1 and remained at a significant high level on Day 2 in I/R rats. Renal vanin-1 protein decreased on Days 1 and 3. In line with these findings, immunofluorescence staining demonstrated that vanin-1 was attenuated in the renal proximal tubules of I/R rats. Our in vitro results confirmed that the supernatant from HK-2 cells under hypoxia/reoxygenation included significantly higher levels of vanin-1 as well as KIM-1 and NGAL. In conclusion, our results suggest that urinary vanin-1 might be a potential novel biomarker of AKI induced by I/R.

Nephrotoxicity Biomarkers: Role and Significance in the Diagnosis of Drug-Induced Kidney Injury

Drug-induced kidney injury (DIKI) accounts for 8 to 60% of episodes of acute kidney injury (AKI) among hospital patients. Early DIKI detection and timely adjustment of therapy will help reduce the kidney injury incidence and mortality. The aim of the study was to analyse scientific literature on the biomarkers used in DIKI diagnosis. The study revealed that the use of such kidney damage markers as serum creatinine, urinary output, urea nitrogen, sodium excretion, urinary sediment microscopy is limited because they do not give a full picture of the kidney injury degree and progression and do not allow for early AKI diagnosis. It was demonstrated that some of the most promising biomarkers are KIM-1, L-FABP, NAG, NGAL, cystatin C, clusterin, β2-microglobulin, МСР-1, IGFBP7, and TIMP-2. However, recommendations for determination of these biomarkers’ urine or blood concentrations for AKI diagnosis are somewhat preliminary, because there have been insufficient clinical and preclinical studies to establish validity of such tests. No precise algorithms based on determination of the biomarkers levels in urea and/or blood serum have been developed for AKI risk assessment, diagnosis, monitoring, and treatment. Thus, further research is necessary to investigate different AKI biomarkers and improve experimental models (both in vivo and in vitro), which will support assessment of potential nephrotoxic properties of existing and new medicinal products.