Urinary Kidney Injury Molecule-1 Research Articles

Magnitude of Urine Albumin and KIM-1 Changes Can be Used to Differentiate Glomerular Injury From Tubular Injury in Rats.

Emerging urinary kidney safety biomarkers have been evaluated in recent years and have been shown to be superior to the serum parameters blood urea nitrogen (BUN) and creatinine (sCr) for monitoring kidney injury in the proximal tubule. However, their potential application in differentiating the location of the initial kidney injury (eg, glomerulus vs tubule) has not been fully explored. Here, we assessed the performance of two algorithms that were constructed using either an empirical or a mathematical model to predict the site of kidney injury using a data set consisting of 22 rat kidney toxicity studies with known urine biomarker and histopathologic outcomes. Two kidney safety biomarkers used in both models, kidney injury molecule 1 (KIM-1) and albumin (ALB), were the best performers to differentiate glomerular injury from tubular injury. The performance of algorithms using these two biomarkers against the gold standard of kidney histopathologic examination showed high sensitivity in differentiating the location of the kidney damage to either the glomerulus or the proximal tubules. These data support the exploration of such an approach for use in clinical settings, leveraging urinary biomarker data to aid in the diagnosis of either glomerular or tubular injury where histopathologic assessments are not conducted.

The use of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for diagnosis of hepato-renal syndrome in advanced cirrhotic patients

The use of urinary kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin for diagnosis of hepato-renal syndrome in advanced cirrhotic patients

Female protection against diabetic kidney disease is regulated by kidney-specific AMPK activity.

Reduced kidney AMPK activity is associated with nutrient stress-induced chronic kidney disease (CKD) in male mice. In contrast, female mice resist nutrient stress-induced CKD. The role of kidney AMPK in sex-related organ protection against nutrient stress and metabolite changes were evaluated in diabetic kidney tubule-specific AMPKγ2KO (KTAMPKγ2KO) male and female mice. In WT males, diabetes increased albuminuria, urinary kidney injury molecule-1, hypertension, kidney p70S6K phosphorylation, and kidney matrix accumulation; these features were not exacerbated with KTAMPKγ2KO. Whereas WT females had protection against diabetes induced kidney injury, KTAMPKγ2KO led to loss of female protection against kidney disease. 17β-estradiol ameliorated high glucose-induced AMPK inactivation, p70S6K phosphorylation and matrix protein accumulation in kidney tubule cells. The mechanism for female protection against diabetes-induced kidney injury is likely via an estrogen-AMPK pathway, as inhibition of AMPK led to loss of estrogen protection to glucose-induced mTORC1 activation and matrix production. RNA-seq and metabolomic analysis identified a decrease in the degradation pathway of phenylalanine and tyrosine resulting in increased urinary phenylalanine and tyrosine levels in females. The metabolite levels correlated with loss of female protection. The findings provide new insights to explain evolutionary advantages to females during states of nutrient challenges.

Mitochondrial DNA and Inflammation Are Associated with Cerebral Vessel Remodeling and Early Diabetic Kidney Disease in Patients with Type 2 Diabetes Mellitus.

Cerebrovascular disease accounts for major neurologic disabilities in patients with type 2 diabetes mellitus (DM). A potential association of mitochondrial DNA (mtDNA) and inflammation with cerebral vessel remodeling in patients with type 2 DM was evaluated. A cohort of 150 patients and 30 healthy controls were assessed concerning urinary albumin/creatinine ratio (UACR), synaptopodin, podocalyxin, kidney injury molecule-1 (KIM-1), N-acetyl-β-(D)-glucosaminidase (NAG), interleukins IL-17A, IL-18, IL-10, tumor necrosis factor-alpha (TNFα), intercellular adhesion molecule-1 (ICAM-1). MtDNA-CN and nuclear DNA (nDNA) were quantified in peripheral blood and urine by qRT-PCR. Cytochrome b (CYTB) gene, subunit 2 of NADH dehydrogenase (ND2), and beta 2 microglobulin nuclear gene (B2M) were assessed by TaqMan assays. mtDNA-CN was defined as the ratio of the number of mtDNA/nDNA copies, through analysis of the CYTB/B2M and ND2/B2M ratio; cerebral Doppler ultrasound: intima-media thickness (IMT)-the common carotid arteries (CCAs), the pulsatility index (PI) and resistivity index (RI)- the internal carotid arteries (ICAs) and middle cerebral arteries (MCAs), the breath-holding index (BHI). The results showed direct correlations of CCAs-IMT, PI-ICAs, PI-MCAs, RI-ICAs, RI-MCAs with urinary mtDNA, IL-17A, IL-18, TNFα, ICAM-1, UACR, synaptopodin, podocalyxin, KIM-1, NAG, and indirect correlations with serum mtDNA, IL-10. BHI correlated directly with serum IL-10, and serum mtDNA, and negatively with serum IL-17A, serum ICAM-1, and NAG. In neurologically asymptomatic patients with type 2 DM cerebrovascular remodeling and impaired cerebrovascular reactivity may be associated with mtDNA variations and inflammation from the early stages of diabetic kidney disease.

Determination of the reference interval for urine kidney injury molecule-1 in 50 healthy cats.

The aim of the present study was to establish a reference interval (RI) for urine kidney injury molecule-1 (KIM-1) in healthy cats. History, physical examination, blood pressure, and feline immunodeficiency virus and feline leukemia virus serology status were determined. A complete blood cell count, serum biochemical profile, urinalysis and kidney ultrasound were performed, and N-terminal pro-brain natriuretic peptide, total thyroxine (TT4) and urine KIM-1 were measured. An RI was calculated and the effect of age, sex, body condition score (BCS), blood pressure, symmetric dimethylarginine (SDMA), serum creatinine concentration (SCr), phosphorus, TT4, urine specific gravity (USG) and mid-sagittal kidney length on urine KIM-1 was evaluated using a general linear model. Of 69 recruited cats, 50 met the inclusion criteria. There were 35 male cats and 15 female cats, with a median age of 4.3 years (range 1.0-12.3), median weight of 5.11 kg (range 2.52-8.45) and median BCS of 6/9 (range 3-8). The median serum concentrations were SDMA 11.0 µg/dl (range 2-14), SCr 88.5 µmol/l (range 47-136), phosphorus 1.41 mmol/l (range 0.8-2.2) and TT4 32.0 nmol/l (range 17-51). Median USG was 1.057 (range 1.035-1.076), mid-sagittal left kidney length was 3.50 cm (range 2.94-4.45) and mid-sagittal right kidney length was 3.70 cm (range 3.06-4.55). The derived RI for urine KIM-1 was 0.02-0.68. USG was a significant (P <0.001) predictor of urine KIM-1. Individually, age, sex, blood pressure, BCS, SDMA, SCr, phosphorus, TT4 and mid-sagittal kidney length were not significant predictors of urine KIM-1. In a multivariate model, if combined with USG, SDMA concentration was predictive (P = 0.030) of urine KIM-1. Urine concentration was significantly correlated with urine KIM-1, which will be an important consideration when interpreting findings in cats with potential kidney injury.

Urine Biomarkers of Kidney Tubule Health and Risk of Incident CKD in Persons Without Diabetes: The ARIC, MESA, and REGARDS Studies

Rationale & ObjectiveTubulointerstitial damage is a feature of early chronic kidney disease (CKD), but current clinical tests capture it poorly. Urine biomarkers of tubulointerstitial health may identify risk of CKD. Study DesignProspective cohort (ARIC) and case-cohort (MESA and REGARDS). Setting & ParticipantsAdults with eGFR ≥60 mL/min/1.73m2 and without diabetes in the ARIC, REGARDS, and MESA studies. ExposureBaseline urine monocyte chemoattractant protein-1 (MCP-1), alpha-1-microglobulin (α1m), kidney injury molecule-1 (KIM-1), epidermal growth factor (EGF), and chitinase-3-like protein 1 (YKL-40). OutcomeIncident CKD or ESKD (end-stage kidney disease). Analytical ApproachMultivariable Cox proportional hazards regression for each cohort; meta-analysis of results from all three cohorts. Results872 ARIC participants (444 cases of incident CKD), 636 MESA participants (158 cases), and 924 REGARDS participants (488 cases) were sampled. Across cohorts, mean age ranged from 60±10 to 63±8 years and baseline eGFR ranged from 88±13 to 91±14 mL/min/1.73m2. In ARIC, higher concentrations of urine MCP-1, α1m, and KIM-1 were associated with incident CKD. In MESA, higher concentration of urine MCP-1 and lower concentration of EGF was each associated with incident CKD. In REGARDS, none of the biomarkers were associated with incident CKD. In meta-analysis of all three cohorts, each two-fold higher α1m concentration was associated with incident CKD (HR=1.19 [1.08, 1.31]). LimitationsObservational design susceptible to confounding; competing risks during long follow-up period; meta-analysis limited to three cohorts. ConclusionsIn three combined cohorts of adults without prevalent CKD or diabetes, higher urine α1m was independently associated with incident CKD. Four biomarkers were associated with incident CKD in at least one of the cohorts when analyzed individually. Kidney tubule health markers might inform CKD risk independent of eGFR and albuminuria.

Urine biomarkers of acute kidney injury and association with brain MRI abnormalities in neonatal hypoxic-ischemic encephalopathy.

Determine whether urine biomarkers NGAL (neutrophil gelatinase-associated lipocalin), KIM-1 (kidney injury molecule 1) and IL-18 (interleukin-18) are associated with abnormal MRI findings in neonates with hypoxic-ischemic encephalopathy (HIE) who underwent therapeutic hypothermia (TH). Secondary analysis of a multicenter, prospective study of neonates with HIE requiring TH. Urine biomarkers were obtained at 12 and 24 h of life (HOL). Brain MRI was scored per NICHD criteria. Association between biomarkers and MRI stage was determined. In 57 neonates with HIE, only IL-18 at 24 HOL was significantly increased in neonates with MRI Stage 2B or greater, compared to Stage 2A or less (mean 398.7 vs. 182.9 pg/mL, p = 0.024.) A multivariate model including IL-18 at 24 HOL and 5-min Apgar performed best, with an AUC of 0.84 (SE = 0.07, p = 0.02). Elevated urine IL-18 at 24 HOL was associated with more severe brain MRI abnormalities among neonates with HIE.

Dapagliflozin Reduces Urinary Kidney Injury Biomarkers in Chronic Kidney Disease Irrespective of Albuminuria Level.

The beneficial effects of sodium-glucose cotransporter 2 (SGLT2) inhibitors in patients with chronic kidney disease (CKD) with low albuminuria levels have not been established. This study aimed to compare the effects of dapagliflozin on kidney injury biomarkers in patients with CKD stratified by albuminuria level. We prospectively enrolled healthy volunteers (HVs; n = 20) and patients with CKD (n = 54) with and without diabetes mellitus. Patients with CKD were divided into two age-matched and sex-matched subgroups according to urinary albumin-creatinine ratio (uACR) levels (<300 mg/g and ≥300 mg/g). The CKD group received dapagliflozin (10 mg/day). Urine samples were collected before treatment and after 3 and 6 months of dapagliflozin. Urinary kidney injury molecule-1 (KIM-1), interleukin-1β (IL-1β), and mitochondrial DNA nicotinamide adenine dinucleotide dehydrogenase subunit-1 (mtND1) copy number were measured. The estimated glomerular filtration rate (eGFR) of patients with CKD was lower than that of HVs (P < 0.001). During the study period, eGFR decreased and uACR did not change in the CKD group. Kidney injury markers were significantly elevated in patients with CKD compared with those in HVs. Dapagliflozin reduced urinary KIM-1, IL-1β, and mtDNA copy number in patients with CKD after 6 months of treatment. In further, the levels of urinary KIM-1 and IL-1β, patients with CKD decreased after 6 months of dapagliflozin treatment regardless of albuminuria level. Dapagliflozin reduced urinary kidney injury biomarkers in patients with CKD, regardless of albuminuria level. These findings suggest that SGLT2 inhibitors may also attenuate the progression of low albuminuric CKD.

Systematic Review of Kidney Injury Biomarkers for the Evaluation of CKD of Uncertain Etiology

IntroductionChronic kidney disease of uncertain etiology (CKDu) is an incompletely defined phenotype of CKD affecting young individuals mostly in agricultural communities in Central America and South Asia. CKDu is a diagnosis of exclusion made in individuals from endemic regions. MethodsWe conducted a systematic review of the primary literature on urinary and plasma kidney injury biomarkers measured in the setting of CKDu (through February 2023). Literature was identified via a Web of Science search and hand search of the references of previously identified literature. Search terms included “CKDu,” “Mesoamerican Nephropathy,” “CKD of unknown etiology,” “Chronic Interstitial Nephritis in Agricultural Communities,” “biomarker,” “urin*,” and/or “plasma.” ResultsA total of 25 papers were included. The two most frequently measured biomarkers were urinary kidney injury molecule-1 and urinary neutrophil gelatinase-associated lipocalin. There was substantial variability in study design, laboratory assay methods, and statistical methodology which prohibited meta-analysis. ConclusionBiomarkers that identify tubulointerstitial disease early and accurately may substantially accelerate progress in the study of CKDu and facilitate public health approaches that eventually lead to its prevention and elimination. To date, the literature is limited by relatively small sample sizes and methodological limitations which should be addressed in future studies.

Comparative Levels of Urinary Biomarkers of Renal Injury and Inflammation Among Patients With Diabetic Nephropathy With or Without Hyperuricemia.

The association between hyperuricemia and development of progressive chronic kidney disease has received increasing attention in recent years. Recent preclinical studies have shown that non-crystalline uric acid can induce renal-specific arteriolopathy, leading to renal injury and tubulointerstitial inflammation. We conducted a open-label cross-sectional study of 25 patients with chronic kidney disease stage III (estimated glomerular filtration rate [eGFR], 7.0 mg/dL) levels of serum uric acid. To determine the correlation between hyperuricemia on urinary protein levels and renal disease progression, we retrospectively compared urine protein and eGFR data between the 2 groups. Eleven patients with normal uric acid levels and 14 with hyperuricemia were enrolled. Urinary levels of both kidney injury molecule-1 (KIM-1) and monocyte chemoattractant protein-1 (MCP-1) were significantly higher in patients with hyperuricemia. Among the normouricemic White and African American (AA) subgroups, there was no difference in KIM-1 or MCP-1 levels, whereas KIM-1 levels were significantly higher among hyperuricemic AA patients with hyperuricemia. Urinary protein was significantly higher between Whites and AA patients with serum uric acid level >7.0 mg/dL as well as patients with urinary KIM-1 levels >1000 pg/mg Cr. A trend toward a more rapid decline in eGFR was noted among hyperuricemic AAs; however, this trend was not statistically significant. Patients with type 2 diabetic nephropathy and persistently elevated serum uric acid levels express higher levels of both KIM-1 and MCP-1 reflective of on-going renal injury and inflammation.

Reno-protective effect of protocatechuic acid is independent of sex-related differences in murine model of UUO-induced kidney injury.

Obstructive nephropathy is a condition often caused by urinary tract obstruction either anatomical (e.g., tumors), mechanical (e.g., urolithiasis), or compression (e.g., pregnancy) and can progress to chronic kidney disease (CKD). Studies have shown sexual dimorphism in CKD, where males were found to have amore rapid decline in kidney function following kidney injury compared to age-matched females. Protocatechuic acid (PCA), an anti-oxidant and anti-inflammatory polyphenolic compound, has demonstrated promising effects in mitigating drug-induced kidney injuries. The current study aims to explore sexual dimorphism in kidney injury after unilateral ureteral obstruction (UUO) and assess whether PCA treatment can mitigate kidney injury in both sexes. UUO was induced in 10-12weeks old male and female C57BL/6J mice. Mice were categorized into four groups (n = 6-8/group); Sham, Sham plus PCA (100mg/kg, I.P daily), UUO, and UUO plus PCA. After 2 weeks of induction of UUO, markers of kidney oxidative stress (TBARs), inflammation (IL-1α and IL-6), tubular injury (neutrophil gelatinase-associated lipocalin, NGAL and urinary kidney injury molecule-1, KIM-1), fibrosis (Masson's trichrome staining, collagen IV expression, MMP-2 and MMP-9) and apoptosis (TUNEL+ cells, active caspase-1 and caspase-3) were significantly elevated in both males and females relative to their sham counterparts. Males exhibited significantly greater kidney oxidative stress, inflammation, fibrosis, and apoptosis after induction of UUO when compared to females. PCA treatment significantly attenuated UUO-induced kidney injury, inflammation, fibrosis, and apoptosis in both sexes. Our findings suggest adifferential gender response to UUO-induced kidney injury with males being more sensitive to UUO-induced kidney inflammation, fibrosis, and apoptosis than age-matched females. Importantly, PCA treatment reduced UUO-induced kidney injury in a sex-independent manner which might be attributed to its anti-oxidant, anti-inflammatory, anti-fibrotic, and anti-apoptotic properties.

The Role of urinary kidney injury molecule 1 (KIM-1) in monitoring the treatment response in Egyptian Lupus Nephritis Patients

Lupus nephritis (LN) affects almost two-thirds of systemic lupus erythematosus (SLE) patients. Despite initial aggressive therapy, up to 25% of patients with LN will progress to permanent renal damage. Conventional serum markers for LN lack the sensitivity of an ideal biomarker. Urinary kidney injury molecule-1 (UKIM-1) is an excellent biomarker for early diagnosis of acute kidney injury and predicting renal outcomes. This study intended to determine the predictive performance of UKIM-1 among LN patients in response to induction therapy by assessing and correlating its levels with renal disease activity. The study included 60 SLE patients divided into 20 SLE patients with active lupus nephritis, 20 SLE patients with inactive lupus nephritis, and 20 lupus patients without nephritis as controls. The study was completed after six months from induction treatment. UKIM-1 was measured by an enzyme linked immunosorbent assay at baseline, three-month follow-up and after complete induction therapy. At baseline, the mean serum creatinine and mean UKIM-1 were 1.7 ±0.7 mg/dL and 10.3 ±1.2 ng/dL, respectively in active LN patients. The mean UKIM-1 levels of complete response and partial response groups were 9.8 ±0.9 ng/mL and 11.3 ±1.0 ng/mL respectively. Based on receiver operating characteristics curve analysis, we found a better diagnostic performance of UKIM-1 to predict response to induction treatment, outperforming conventional biomarkers. The sensitivity and specificity were 84.6% and 85.7 %, respectively at an area under the curve of 0.896 and the best cut-off level was ≤10.6 ng/mL. In conclusion, UKIM-1 performed better than conventional biomarkers in predicting response to treatment of active LN.

Study of Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule-1 in Patients with Type 2 Diabetes Mellitus Nephropathy.

There is a need for accurate and rapid biomarkers for the early diagnosis of diabetic nephropathy (DN). We aimed to study the accuracy of urinary neutrophil gelatinase-associated lipocalin (uNGAL), urinary kidney injury molecule-1 (uKIM-1), and blood NGAL (bNGAL) in type 2 diabetics as biomarkers for diagnosis of DN. The study was a retrospective case-control study that included 30 control subjects, 40 diabetics with normo-albuminuria < 30 mg/g and eGFR > 60 mL/minute/1.73 m2, and 30 diabetics with albuminuria > 30mg/g and eGFR < 60mL/minute/1.73 m2. Blood and urine samples were obtained to determine levels of bNGAL, uNAGAL, and uKIM1. There was a significant increase in bNGAL, uNGAL, uKIM 1, uNGAL/creatinine and uKIM 1/creatinine among diabetics with albuminuria compared to diabetics with normoalbuminuria and normal control (p < 0.001 for all markers). For diagnosis of early DN, both bNGAL and uKIM 1 had sensitivity and specificity of 100% for each at cutoff values of 322.5 pg/mL and 74.25 ng/mL, respectively. uNGAL had a sensitivity of 97.5% and a spec-ificity of 100% at a cutoff point of 565 ng/mL. uKIM1/creatinine at a cutoff of 51.2 had a sensitivity of 100% and specificity of 100%. The present study highlights the accuracy of urinary KIM1 and NGAL and blood NGAL as biomarkers for the diagnosis of nephropathy in the early stage of diabetic nephropathy. There were positive correlations with kidney function tests creatinine, blood urea nitrogen, and the presence of albuminuria.

Biomarkers for Diabetic Nephropathy with a Focus on Kidney Injury Molecule-1 (KIM-1).

Diabetic Nephropathy (DN), with an increasing rate of mortality and morbidity, is considered the main cause of End-Stage Renal Disease (ESRD). A wide spectrum of biomarkers exist for early detection of DN, but they suffer from low specificity and sensitivity, indicating the urgent demand for finding more effective biomarkers. Also, the pathophysiology of tubular damage and its relation to DN are not yet completely understood. Kidney Injury Molecule-1 (KIM-1) is a protein that is expressed at substantially low contents in the kidney under physiological conditions. A number of reports have demonstrated the close relationship between urine and tissue KIM-1 levels and kidney disorders. KIM-1 is known as a biomarker for diabetic nephropathy and renal injury. In this study, we aim to review the potential clinical and pathological roles of KIM-1 in diabetic nephropathy.

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

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

SGLT2 inhibitor dapagliflozin protects the kidney in a murine model of Balkan nephropathy.

Proximal tubular uptake of aristolochic acid (AA) forms aristolactam (AL)-DNA adducts, which cause a p53/p21-mediated DNA damage response and acute tubular injury. Recurrent AA exposure causes kidney function loss and fibrosis in humans (Balkan endemic nephropathy) and mice and is a model of (acute kidney injury) AKI to chronic kidney disease (CKD) transition. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. C57BL/6J mice (15-wk-old) were administered vehicle or AA every 3 days for 3 wk (10 and 3 mg/kg ip in females and males, respectively). Dapagliflozin (dapa, 0.01 g/kg diet) or vehicle was initiated 7 days prior to AA injections. All dapa effects were sex independent, including a robust glycosuria. Dapa lowered urinary kidney-injury molecule 1 (KIM-1) and albumin (both normalized to creatinine) after the last AA injection and kidney mRNA expression of early DNA damage response markers (p53 and p21) 3 wk later at the study end. Dapa also attenuated AA-induced increases in plasma creatinine as well as AA-induced up-regulation of renal pro-senescence, pro-inflammatory and pro-fibrotic genes, and kidney collagen staining. When assessed 1 day after a single AA injection, dapa pretreatment attenuated AL-DNA adduct formation by 10 and 20% in kidney and liver, respectively, associated with reduced p21 expression. Initiating dapa application after the last AA injection also improved kidney outcome but in a less robust manner. In conclusion, the first evidence is presented that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.NEW & NOTEWORTHY Recurrent exposure to aristolochic acid (AA) causes kidney function loss and fibrosis in mice and in humans, e.g., in the form of the endemic Balkan nephropathy. Inhibitors of the proximal tubule sodium-glucose transporter SGLT2 can protect against CKD progression, but their effect on AA-induced kidney injury remains unknown. Here we provide the first evidence in a murine model that pretreatment with an SGLT2 inhibitor can attenuate the AA-induced DNA damage response and subsequent nephropathy.

Predictive Capacity of Plasma and Urinary Biomarkers for Persistent Albuminuria in Patients with Sickle Cell Disease

Introduction: Chronic kidney disease (CKD) is common in sickle cell disease (SCD) and is associated with increased mortality and morbidity. As albuminuria and changes in estimated glomerular filtration rate (eGFR) occur well after substantial structural and functional tissue damage have occurred, novel biomarkers are needed to predict CKD prior to its development. In this multicenter study, we investigated the association of multiple plasma and urine biomarkers with persistent albuminuria (PA) and their potential in predicting PA in patients with SCD. Methods: Adult subjects with HbSS or HbSb 0 thalassemia were enrolled in a prospective, longitudinal cohort study of CKD in SCD. We excluded patients with diabetic nephropathy, cancer, connective tissue disease, other glomerular diseases, end-stage kidney disease on dialysis, known infection with hepatitis (B or C) or HIV, and who had undergone bone marrow transplantation and solid organ transplantation. Participants were enrolled during routine clinical visits in the non-crisis, “steady states.” PA was defined as at least 2 of 3 spot urine albumin-creatinine ratio (ACR) values ≥30 mg/g or a single value ≥100 mg/g. At baseline evaluation, plasma was analyzed for biomarkers of coagulation activation (D-dimer, thrombin antithrombin complex [TAT], ratio of cleaved high molecular weight kininogen-to-intact high molecular weight kininogen [cHK/iHK]), endothelial dysfunction (endothelin-1 [ET1], vascular endothelial growth factor [VEGF], vascular cell adhesion molecule-1 [VCAM-1]), and urine was analyzed for kidney injury molecule 1 (KIM-1), nephrin and angiotensinogen (AGT) using commercially available ELISA. All urinary biomarkers were normalized to urine creatinine. For baseline values, a standard t-test was performed for continuous variables and a chi-square test was performed for categorical variables. Logistic regression analysis was performed to assess univariate predictors of research biomarkers for PA. Results: Of 278 evaluated subjects, 104 (37.4 %) had PA with a median ACR of 194.5 mg/g [IQR: 102.4, 487.1], and 174 subjects (62.6 %) did not have PA (non-PA) with a median ACR of 13.0 mg/g [IQR: 7.4, 22.4]. Subjects with PA were older, had lower hemoglobin and fetal hemoglobin, but higher systolic and diastolic blood pressures than those without PA (Table 1). Plasma VCAM-1, urinary KIM-1, and urinary AGT were significantly associated with PA with odds ratios of 1.001 (AUC: 0.636; 95% CI: 1.00, 1.002), 1.737 (AUC: 0.661; 95% CI: 1.226, 2.575), and 1.053 (AUC: 0.71; 95% CI: 1.029, 1.084), respectively (Table 2). Surprisingly, ET1 and urinary nephrin-creatinine ratio were not significantly associated with PA in this cohort. Conclusion: Urinary AGT exhibited the highest sensitivity for PA, while urinary KIM-1 was the most specific. The relatively modest sensitivity of KIM-1, a marker of renal tubular dysfunction, is likely because albuminuria in SCD results from both glomerular and tubular dysfunction. These results highlight the potential importance of urinary AGT as a key biomarker in identifying individuals at risk for PA. Our ongoing studies will evaluate the predictive capacity of these biomarkers for development of PA in SCD.

A clinically-relevant mouse model that displays hemorrhage exacerbates tourniquet-induced acute kidney injury.

Hemorrhage is a leading cause of death in trauma. Tourniquets are effective at controlling extremity hemorrhage and have saved lives. However, tourniquets can cause ischemia reperfusion injury of limbs, leading to systemic inflammation and other adverse effects, which results in secondary damage to the kidney, lung, and liver. A clinically relevant animal model is critical to understanding the pathophysiology of this process and developing therapeutic interventions. Despite the importance of animal models, tourniquet-induced lower limb ischemia/reperfusion (TILLIR) models to date lack a hemorrhage component. We sought to develop a new TILLIR model that included hemorrhage and analyze the subsequent impact on kidney, lung and liver injuries. Four groups of mice were examined: group 1) control, group 2) hemorrhage, group 3) tourniquet application, and group 4) hemorrhage and tourniquet application. The hemorrhagic injury consisted of the removal of 15% of blood volume through the submandibular vein. The tourniquet injury consisted of orthodontic rubber bands applied to the inguinal area bilaterally for 80min. Mice were then placed in metabolic cages individually for 22h to collect urine. Hemorrhage alone did not significantly affect transcutaneous glomerular filtration rate (tGFR), blood urea nitrogen (BUN) or urinary kidney injury molecule-1 (KIM-1) levels. Without hemorrhage, TILLIR decreased tGFR by 46%, increased BUN by 162%, and increased KIM-1 by 27% (p < 0.05 for all). With hemorrhage, TILLIR decreased the tGFR by 72%, increased BUN by 395%, and increased urinary KIM-1 by 37% (p < 0.05 for all). These differences were statistically significant (p < 0.05). While hemorrhage had no significant effect on TILLIR-induced renal tubular degeneration and necrosis, it significantly increased TILLIR-induced lung total injury scores and congestion, and fatty liver. In conclusion, hemorrhage exacerbates TILLIR-induced acute kidney injury and structural damage in the lung and liver.

Hypohydration induced by prolonged cycling in the heat increases biomarkers of renal injury in males

PurposeRecent studies have shown that hypohydration can increase renal injury. However, the contribution of hypohydration to the extent of renal injury is often confounded by exercise induced muscle damage. Therefore, the aim of the present study was to investigate the effect of manipulating hydration status during moderate-intensity cycling in the heat on biomarkers of renal injury.MethodsFollowing familiarisation, fourteen active males (age: 21 [20–22] y; BMI: 22.1 ± 1.9 kg/m2; V˙\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$ \\dot{V} $$\\end{document}O2peak: 55 ± 9 mL/kg/min) completed two experimental trials, in a randomised cross-over design. Experimental trials consisted of up to 120 min of intermittent cycling (~ 50% Wpeak) in the heat (~ 35 °C, ~ 50% relative humidity). During exercise, subjects consumed either a water volume equal to 100% body mass losses (EU) or minimal water (HYP; 75–100 mL) to induce ~ 3% body mass loss. Blood and urine samples were collected at baseline, 30 min post-exercise and 24 h post-baseline, with an additional urine sample collected immediately post-exercise.ResultsThirty minutes post-exercise, body mass and plasma volume were lower in HYP than EU (P < 0.001), whereas serum and urine osmolality (P < 0.001), osmolality-corrected urinary kidney injury molecule-1 concentrations (HYP: 2.74 [1.87–5.44] ng/mOsm, EU: 1.15 [0.84–2.37] ng/mOsm; P = 0.024), and percentage change in osmolality-corrected urinary neutrophil gelatinase-associated lipocalin concentrations (HYP: 61 [17–141] %, EU: 7.1 [– 4 to 24] %; P = 0.033) were greater in HYP than EU.ConclusionHypohydration produced by cycling in the heat increased renal tubular injury, compared to maintaining euhydration with water ingestion.

A comparison with micro albuminuria indicates whether urine and serum kidney injury molecule-1 can predict the onset of early diabetic nephropathy (DN).

Diabetic nephropathy (DN) is the most frequent consequence of DM and a significant contributor to chronic kidney disease, a multifactorial illness. Kidney injury molecule-1 (KIM-1) is a sensitive and accurate indicator of kidney damage and a predictive indicator. Aim: The present investigation aimed to examine serum and urine KIM-1 as a DN early marker. Patients and methods: The present study included 150 participants, among whom 50 non-diabetic participants were chosen as controls. One hundred diabetic participants were split into two groups based on their urine albumin/creatinine ratio (ACR) as participants with normoalbuminuria (T2DM patients without nephropathy) and microalbuminuria (T2DM patients with nephropathy). The blood glucose, HbA1c, s.urea, and creatinine levels in serum and urine were measured using standard laboratory techniques, and Elisa Essay measured serum and urine KIM-1 levels. Results: There was a distinct variation in the mean serum and urine KIM-1 between the control and diabetics without microalbuminuria (P = 0.001). Serum KIM-1 correlated with ACR (P = 0.669) in people with diabetes with microalbuminuria. Urine KIM-1 was less correlated than serum KIM-1 (p = 0.257). A strong association was found between ACR and serum KIM1 in people with diabetes with microalbuminuria and a low correlation between ACR and urine KIM-1 in people with diabetes with microalbumin. Conclusion: According to the current investigation, diabetic groups with microalbuminuria had higher serum and urine levels of KIM-1 than the control groups. Additionally, there was a favorable correlation between serum KIM-1 and the length of diabetes. More extensive multicentric trials are also needed to assess the efficacy of serum and urine KIM-1 as a DN early marker. Keywords: Serum /Urine KIM-1; Dibetic nephropathy; Microalbumin; DM type2