Urinary Kidney Injury Molecule-1 Research Articles

Urinary microRNAs miR-15b and miR-30a as novel noninvasive biomarkers for gentamicin-induced acute kidney injury

MicroRNAs serve as potential biomarkers in various pathological models, and are stable and detectable in biofluids. We investigated the urinary microRNA expression profile in a gentamicin-induced acute kidney injury canine model using RNA sequencing. A total of 234 differentially expressed microRNAs were screened after 12 consecutive days of gentamicin administration (P < 0.05). Six candidate microRNAs (miR-15b, -15b-3p, -16, -30a, -30a-3p, and -30c-2-3p) were selected according to a set criterion, and validated by real-time quantitative PCR. The diagnostic values of these six candidate microRNAs were better than the traditional serum biomarkers (all P < 0.05). Further, using receiver operating characteristic curve analysis, we found that miR-15b and -15b-3p were superior to urinary kidney injury molecule-1 (both P < 0.05). Moreover, miR-15b and -30a levels in the urine samples significantly correlated with their respective levels in the kidney tissue samples (r=0.512 and 0.505, respectively, both P < 0.05). Our data concluded that miR-15b and -30a may be promising biomarkers for renal toxicity.

Value of urinary kidney injury molecule-1 levels in predicting acute kidney injury in very low birth weight preterm infants.

ObjectiveThis study aimed to evaluate the significance of urinary kidney injury molecule-1 (uKIM-1) levels in predicting acute kidney injury (AKI) and mortality in very low birth weight (VLBW) preterm infants.MethodsThis prospective, observational cohort study was conducted on 39 VLBW preterm infants. Serum creatinine (SCr) and uKIM-1 levels were measured in the first 24 and 48 to 72 hours of life. The estimated glomerular filtration rate (eGFR) was calculated. Levels of uKIM-1 were measured with an enzyme-linked immunosorbent assay.ResultsAmong 39 VLBW infants, 9 (23%) developed AKI. The mortality rate was 17.9% (n = 7 neonates). There was no significant difference in SCr levels, uKIM-1 levels, or the eGFR obtained in the first 24 hours in the AKI group compared with controls. However, significant differences were found in SCr and uKIM-1 levels, and the eGFR rate at 48 to 72 hours between the groups. Levels of uKIM-1 were significantly higher in non-survivors than in survivors in the first 24 and 48 to 72 hours of life.ConclusionThe level of uKIM-1 can be used as a simple noninvasive diagnostic method for predicting AKI and mortality, especially within 48 to 72 hours of life.Clinical trial registration: We do not have a clinical trial registration ID. In Turkey, clinical trial registration is not required for non-drug, noninvasive, clinical studies.

The Pattern of Cyclosporine Nephrotoxicity and Urinary Kidney Injury Molecule 1 in Allogenic Hematopoietic Stem Cell Transplant Patients

The typical immunosuppressive regimen of hematopoietic stem cell transplant includes cyclosporine. However, cyclosporine nephrotoxicity is a concern. We studied cyclosporine nephrotoxicity epidemiology in hematopoietic stem cell transplant patients and compared the pattern and urinary levels of the KIM-1 kidney injury molecule versus serum and urine creatinine levels. The study covered 10 months at Namazi Hospital, Shiraz, Iran. All patients met the following criteria: > 15 years old, received allogenic hematopoietic stem cell transplant without history of acute or chronic kidney disease, and scheduled for at least 1 week of cyclosporine treatment. Urinary and serum levels of creatinine, urea, sodium, potassium, magnesium, and the KIM-1 kidney injury molecule were measured on days 0, 3, 5, 7, 10, and 14 of cyclosporine treatment. Of 42 patients, one-third developed cyclosporine nephrotoxicity (30.95%), and median onset time was 15 days. Hypokalemia and hypomagnesemia were reported in 76.2% and 53.4% of the cohort, respectively. None of the demographic, clinical, and paraclinical parameters was significantly associated with cyclosporine nephrotoxicity. Median duration of hospital stay for patients with cyclosporine nephrotoxicity (41 days) was significantly higher (P < .001) than those without nephrotoxicity (29 days). Area under the curve for receiver operating characteristic showed that accuracy of serum creatinine (0.267; 95% CI, 0.11-0.43) at day 0 of cyclosporine treatment was significantly lower (P = .017) than the accuracy of urine creatinine (0.477; 95% CI, 0.28-0.67) and urine levels of the KIM-1 kidney injury molecule (0.594; 95% CI, 0.41-0.78). Cyclosporine nephrotoxicity is a common adverse effect in the setting of hematopoietic stem cell transplant and occurs mostly within the first 2 weeks of cyclosporine treatment. Urine KIM-1 kidney injury molecule measurement had no overall superiority and no improved accuracy over serum or urine creatinine measurements for prediction or detection of cyclosporine nephrotoxicity.

KIM-1 (kidney injury molecule 1) in the urine of renal cell carcinoma patients

Objective: to assess the potential clinical significance of KIM-1 (kidney injury molecule 1) as a urinological marker for kidney cancer.Materials and methods. An enzyme-linked immunosorbent assay was used to assess urinary KIM-1 (uKIM-1 — kidney injury molecule 1) levels in 67 patients with renal cell carcinoma (RCC) and 36 healthy volunteers (a control group).Results. Both in patients and in healthy individuals, uKIM-1 levels were age independent. A difference between mean uKIM-1 values in RCC patients (2.4 ± 0.2 ng/ml) and the control group (0.7 ± 0.1 ng/ml) was statistically significant (p &lt;0.0001). In RCC patients the higher uKIM-1 level was observed at more advanced clinical disease stages: the values increasedfrom 2.0 ± 0.2 ng/ml at the stage I and 3.0 ± 0.5 ng/ml at the stage II—III to 4.4 ± 1.2 ng/ml at the stage IV. In the group of patients with stage IRCC, most representative by the number of cases (n = 44) the uKIM-1 levels correlated with the tumor size and were increased in patients with different histological subtypes of the tumor, including clear cell, papillary and chromophobe RCC. After nephrectomy, a monotonous decrease in uKIM-1 level was observed, and after 6 days its values approached the mean value in the control group. Two days after kidney resection, uKIM-1 increased and then decreased, remaining elevated after 6 days.Conclusion. This study demonstrates that uKIM-1 can be attributed to potentially significant urine tumor-associated markers of RCC.

Diagnostic Performance of Biomarkers Urinary KIM-1 and YKL-40 for Early Diabetic Nephropathy, in Patients with Type 2 Diabetes: A Systematic Review and Meta-Analysis.

There is a lack of prediction markers for early diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM). The aim of this systematic review and meta-analysis was to evaluate the performance of two promising biomarkers, urinary kidney injury molecule 1 (uKIM-1) and Chitinase-3-like protein 1 (YKL-40) in the diagnosis of early diabetic nephropathy in type 2 diabetic patients. A comprehensive search was performed on PubMed by two reviewers until May 2020. For each study, a 2 × 2 contingency table was formulated. Sensitivity, specificity, and other estimates of accuracy were calculated using the bivariate random effects model. The hierarchical summary receiver operating characteristic curve hsROC) was used to pool data and evaluate the area under curve (AUC). The sources of heterogeneity were explored by sensitivity analysis. Publication bias was assessed using Deek’s test. The meta-analysis enrolled 14 studies involving 598 healthy individuals, 765 T2DM patients with normoalbuminuria, 549 T2DM patients with microalbuminuria, and 551 T2DM patients with macroalbuminuria, in total for both biomarkers. The AUC of uKIM-1 and YKL-40 for T2DM patients with normoalbuminuria, was 0.85 (95%CI; 0.82–0.88) and 0.91 (95%CI; 0.88–0.93), respectively. The results of this meta-analysis suggest that both uKIM-1 and YKL-40 can be considered as valuable biomarkers for the early detection of DN in T2DM patients with the latter showing slightly better performance than the former.

Beyond the tubule: pathological variants of LRP2, encoding the megalin receptor, result in glomerular loss and early progressive chronic kidney disease.

Pathogenic variants in the LRP2 gene, encoding the multiligand receptor megalin, cause a rare autosomal recessive syndrome: Donnai-Barrow/Facio-Oculo-Acoustico-Renal (DB/FOAR) syndrome. Because of the rarity of the syndrome, the long-term consequences of the tubulopathy on human renal health have been difficult to ascertain, and the human clinical condition has hitherto been characterized as a benign tubular condition with asymptomatic low-molecular-weight proteinuria. We investigated renal function and morphology in a murine model of DB/FOAR syndrome and in patients with DB/FOAR. We analyzed glomerular filtration rate in mice by FITC-inulin clearance and clinically characterized six families, including nine patients with DB/FOAR and nine family members. Urine samples from patients were analyzed by Western blot analysis and biopsy materials were analyzed by histology. In the mouse model, we used histological methods to assess nephrogenesis and postnatal renal structure and contrast-enhanced magnetic resonance imaging to assess glomerular number. In megalin-deficient mice, we found a lower glomerular filtration rate and an increase in the abundance of injury markers, such as kidney injury molecule-1 and N-acetyl-β-d-glucosaminidase. Renal injury was validated in patients, who presented with increased urinary kidney injury molecule-1, classical markers of chronic kidney disease, and glomerular proteinuria early in life. Megalin-deficient mice had normal nephrogenesis, but they had 19% fewer nephrons in early adulthood and an increased fraction of nephrons with disconnected glomerulotubular junction. In conclusion, megalin dysfunction, as present in DB/FOAR syndrome, confers an increased risk of progression into chronic kidney disease.

Biomarkers of high salt intake.

High salt intake is associated with hypertension, which is a leading modifiable risk factor for cardiovascular disease (CVD) and chronic kidney disease (CKD). International Guidelines recommend a large reduction in the consumption of sodium to reduce blood pressure, organ damage, and mortality. In its early stages, the symptoms of CKD are generally not apparent. CKD proceeds in a "silent" manner, necessitating the need for urinary biomarkers to detect kidney damage at an early stage. Since traditional renal biomarkers, such as serum creatinine, are not sufficiently sensitive, difficulties are associated with detecting kidney damage induced by a high salt intake, particularly in normotensive individuals. Several new biomarkers for renal tubular damage, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), vanin-1, liver-type fatty acid-binding protein (L-FABP), and monocyte chemotactic protein-1 (MCP-1), have recently been identified. However, few studies have investigated early biomarkers for CKD progression associated with a high salt diet. This chapter provides insights into novel biomarkers for CKD in normo- and hypertensive individuals with a high salt intake. Recent studies using spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) fed a high salt diet identified urinary vanin-1 and NGAL as early biomarkers for renal tubular damage in SHR and WKY, whereas urinary KIM-1 was a useful biomarker for salt-induced renal injury in SHR only. Clinical studies are needed to confirm these findings.

Can serum Neutrophil Gelatinase Associated Lipocalin and Kidney Injury Molecule−1 help in decision making for surgery in antenatally dedected hydronephrosis

Congenital obstructive uropathies are among leading reasons for renal failure in children. Answers to questions such as what the critical threshold of obstruction is or which degree of obstruction disrupts the development of the kidney still remain unclear. Several biomarkers such as Kidney Injury Molecule 1 (KIM-1) and Neutrophil Gelatinase Associated Lipocalin (NGAL) may help clinicians in the clinical evaluation and appropriate planning of the disease. This study aimed to investigate whether serum and urinary KIM-1 and NGAL levels contribute to conventional methods in decision-making for surgery in the postnatal period of infants with antenatal hydronephrosis. 34 patients with the diagnosis of antenatal hydronephrosis were evaluated prospectively. Renal pelvis diameters of all patients were above 10mm in the ultrasonography (USG). Patients underwent diuretic renal scintigraphy after neonatal period. Patients were divided into two groups as surgery or follow-up based on USG and scintigraphy findings. Blood and urine samples were collected at first visits in both groups and again at the 3. Postoperative month in the surgery group. Serum and urinary NGAL and KIM-1 levels were measured by ELISA method. Study data were compared through the Mann-Whitney U and Wilcoxon Signed-Ranks test. There were 10 patients in the surgery group and 24 patients in the follow-up group. The age and gender did not differ between the groups. The surgery group had significantly higher median serum NGAL values (259.2ng/mL) than that in the follow-up group (46.8ng/mL, p=0.028). The postoperative reduction of the median serum NGAL to 68.1ng/mL compared to preoperative level was also found to be significant (p=0.037) in the surgery group. Between the groups and within the surgery group no statistically significant difference was detected in terms of median urinary NGAL, and serum and urine KIM-1 levels. USG and renal scintigraphy are frequently used in determining whether patients with antenatal hydronephrosis need surgical intervention in the postnatal period. Several new biomarkers might help clinicians in decision making for surgery. KIM-1 and NGAL levels can be measured both in urine and serum. To our knowledge, this is the only study where serum NGAL and KIM-1 levels were measured in patients with antenatal diagnosis. Small sample size, lack of long term findings and control group are limitations of our study. Serum NGAL levels of patients with antenatal hydronephrosis may help in decision making on the surgical intervention.

Urine NGAL and KIM-1: tubular injury markers in acute lymphoblastic leukemia survivors

IntroductionNephrotoxicity is a potential adverse effect of anticancer treatment in childhood. Cytostatics, abdominal radiotherapy, total body irradiation (TBI) and some agents used in supportive care may induce acute kidney injury (AKI) or lead to chronic kidney disease (CKD). The aim of this study was to test the hypothesis whether urinary kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are increased in acute lymphoblastic leukemia (ALL) survivors.MethodThe study cohort consisted of 86 patients (42 females) previously treated for ALL. The median time after cessation of treatment was 6.55 (IQR: 1.96–9.93) years and median age at the time of study: 12 (IQR: 6.76–16.00). The control group included 53 healthy peers. Immunoenzymatic ELISA commercial kits were used to measure urine KIM-1 and NGAL levels.ResultsThe median levels of urine uNGAL (p < 0.05), uNGAL/creatinine (cr.) ratio (p < 0.0001) and uKIM-1/creatinine ratio (p < 0.0001) were significantly higher in ALL survivors in comparison with healthy controls. Female patients had significantly higher levels of NGAL and NGAL/cr. than males (mean 8.42 ± 7.1 vs. 4.59 ± 4.5 ng/mL and 86.57 ± 77 vs. 37.7 ± 37 ng/mg, respectively; p < 0.01). Of all the study participants, 11 (13%) presented eGFR below 90 mL/min/1.73 m2. The NGAL/cr. ratio seemed to be the best predictor of decreased eGFR (AUC = 0.65). The cumulative dose of methotrexate and cyclophosphamide did not predict the values of the urine NGAL, NGAL/cr., KIM-1/cr. and eGFR.Five years after the end of treatment, the patients had higher levels of uKIM-1 (1.02 ± 0.8 vs. 0.62 ± 0.6 ng/mL, p < 0.01), uNGAL (7.9 ± 6.7 vs. 4.6 ± 5 ng/mL, p < 0.01) and lower eGFR (114 ± 29 vs. 134 ± 35 mL/min/1.73 m2, p < 0.01) in comparison with ALL survivors with the observation period of less than 5 years.ConclusionWe demonstrated that ALL survivors have higher levels of urine NGAL, NGAL/cr. and uKIM-1/cr. ratio as compared to the control group. Further long-term follow-up studies are necessary to assess the significance of the NGAL and KIM-1 and their relationship to kidney damage after anticancer treatment in childhood.

Urinary Human Kidney Injury Molecule1- (hKIM1-) is not Increased in Patients with Renal Cell Carcinoma.

Human Kidney Injury Molecule-1 (hKIM-1) was proposed as urinary biomarker of renal cell carcinoma (RCC). The aim of the study was to validate urinary hKIM-1 as a biomarker of RCC. Forty-six participants were enrolled into the study, including 30 patients with clear-cell or papillary RCC and 16 matched patients in the comparison group. Preoperative urinary hKIM-1 levels were measured using commercially available ELISA kit and normalized to urinary creatinine levels. The concentrations of urinary hKIM-1 normalized to urinary creatinine in patients with RCC and comparison group did not differ significantly (1.35 vs. 1.32 ng/mg creatinine, p=.25). There was also no difference in urinary hKIM-1 concentration regarding stage or grade of renal cancer. Additional analysis of patients without chronic kidney disease (defined as eGFR ≥60mL/min/1.73m²) also did not reveal significant difference in urinary hKIM-1 concentrations between the groups (1.54 vs. 1.37; p=.47). Results of our study do not confirm recent suggestions that urinary hKIM-1 may be a biomarker of RCC.

Acute kidney injury during pregnancy leads to increased sFlt-1 and sEng and decreased renal T regulatory cells in pregnant rats with HELLP syndrome

BackgroundThe incidence of acute kidney injury (AKI) during pregnancy precedes a high maternal mortality rate of 20–40%. AKI during pregnancy has multiple etiologies; however, the more common are maternal hypertensive disorders, which include preeclampsia and HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Therefore, we sought to assess the impact of AKI on blood pressure, kidney injury, and anti-angiogenic factors during pregnancies with and without HELLP syndrome.MethodsOn gestational day (GD) 12, mini-osmotic pumps were inserted into a subset of normal pregnant (NP) rats infusing 4.7 μg/kg soluble fms-like tyrosine kinase-1 (sFlt-1) and 7 μg/kg soluble endoglin (sEng) to induce HELLP syndrome. On GD18, the renal pedicles were occluded for 45 min to induce AKI via bilateral ischemia reperfusion in a subset of NP (n = 18) or HELLP (n = 20) rats. Control NP (n = 20) and HELLP (n = 20) rats underwent a SHAM surgery on GD18. Plasma, urine, and maternal organs were saved for further analysis. Renal injury was assessed via renal histopathology, glomerular filtration rate (GFR), T cell infiltration, and assessment of kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Data was measured via two-way analysis of variance with Tukey’s test for post hoc analysis.ResultsBlood pressures were increased in HELLP+AKI rats (p = 0.0001); both NP+AKI and HELLP+AKI rats had increased lactate dehydrogenase (p < 0.0001) and aspartate aminotransferase levels (p < 0.0001), and decreased platelet levels (p < 0.001) vs. NP rats. HELLP+AKI (p = 0.002) and HELLP rats (p = 0.0002) had evidence of renal fibrosis vs. NP rats. GFR was decreased in HELLP+AKI (p = 0.01) rats vs. NP rats. Urinary KIM-1 was increased in NP+AKI rats vs. NP (p = 0.003) and HELLP rats (p = 0.01). HELLP+AKI rats had increased urinary KIM-1 vs. NP (p = 0.0008) and HELLP rats (p = 0.004) and increased NGAL vs. HELLP rats (p = 0.002). HELLP+AKI rats had increased sFlt-1 (p = 0.009) vs. NP rats. NP+AKI (p = 0.02) and HELLP+AKI (p = 0.007) rats had increased sEng vs. NP rats. CD3+CD4+ T cells were significantly increased in HELLP+AKI rats vs. NP (p = 0.0002) and NP+AKI (p = 0.05) rats. T regulatory cells were significantly decreased in HELLP+AKI (p = 0.03) and NP+AKI (p = 0.02) rats vs. NP rats; there were no changes between groups in T helper 17 cells (p = 0.34).ConclusionThe findings in this study suggest that AKI during pregnancy contributes to increased blood pressure and biochemical markers for HELLP syndrome, creates an anti-angiogenic imbalance, and exacerbates kidney injury as shown on histopathology, GFR, and kidney injury markers.

The utility of kidney injury molecule-1 as an early biomarker of kidney injury in people living with HIV.

There are increasing reports of antiretroviral therapy (ART) drug-related kidney dysfunction. Traditional markers of kidney dysfunction such as urine protein/creatinine ratio and estimated glomerular filtration rate (eGFR) have thus far proven ineffective at detecting some sub-clinical forms of ART-related kidney injury. This is a cross-sectional examination of 114 people living with HIV (PLWH), either naïve (N =104) or treatment experienced (N =10). Urinary kidney injury molecule-1 (KIM-1 ng/mg) thresholds were estimated using electrochemiluminescent assays from stored urine samples and normalised for urinary creatinine excretion (KIM-1/Cr). Correlation coefficients and predictors of kidney tubular injury were compared and derived for both adjusted and unadjusted urinary KIM-1/CR (ng/mg). In PLWH (both ART-naïve and treatment experienced) had a higher baseline unadjusted and adjusted median (≥3.7 ng/mg) and upper tertile (≥6.25 ng/mg) urinary KIM-1/Cr levels compared to either non-normal volunteers (0.39 ng/mg) or those with acute kidney injury in the general population (0.57 ng/mg). When upper tertile KIM-1/Cr (≥6.25 ng/mg) was utilised as a marker of kidney injury, eGFR (ml/min/1.73 m2), white Caucasian ethnicity, and protease inhibitor exposure were significantly associated with increased risk of kidney injury in multivariate analyses (odds ratio 0.91, confidence interval [CI] 0.68–0.98, P = 0.02; odds ratio 8.9, CI 1.6–48.6, p = 0.01; and odds ratio 0.05, CI 0.03–0.9, p =0.04, respectively). We found a significant degree of sub-clinical kidney injury (high unadjusted and adjusted KIM-1/Cr) in PLWH with normal kidney function (eGFR ≥60 ml/min/1.73 m2). We also found a higher baseline KIM-1/Cr (ng/mg) in our study cohort than reported both in normal volunteers and patients with kidney injury in the general population.

Ameliorative effect of phosphodiesterase 4 and 5 inhibitors in deoxycorticosterone acetate-salt hypertensive uni-nephrectomized KKAy mice.

Diabetic nephropathy (DN) is a leading cause of end-stage renal disease (ESRD). Hypertension increases kidney stress, which deteriorates function, and leads to peripheral renal vascular resistance. Long-term hypoperfusion promotes interstitial fibrosis and glomerular sclerosis, resulting in nephrosclerosis. Although hypertension and DN are frequent ESRD complications, relevant animal models remain unavailable. We generated a deoxycorticosterone acetate (DOCA)-salt hypertensive uni-nephrectomized (UNx) KKAy mouse model demonstrating hypertension, hyperglycemia, cardiac hypertrophy, kidney failure, increased urinary albumin creatinine ratio (UACR), and increased renal PDE4D and cardiac PDE5A mRNA levels. We hypothesized that the novel PDE4 selective inhibitor, compound A, and PDE5 inhibitor, sildenafil, exhibit nephroprotective, and cardioprotective effects in this new model. Compound A, sildenafil, and the angiotensin II receptor blocker, irbesartan, significantly reduced ventricular hypertrophy and pleural effusion volume. Meanwhile, compound A and sildenafil significantly suppressed the UACR, urinary kidney injury molecule-1, and monocyte chemoattractant protein-1 levels, as well as that of renal pro-fibrotic marker mRNAs, including collagen 1A1, fibronectin, and transforming growth factor-beta (TGF-β). Moreover, compound A significantly suppressed TGF-β-induced pro-fibrotic mRNA expression in vitro in all major kidney lesions, including within the glomerular mesangial region, podocytes, and epithelial region. Hence, PDE4 and PDE5 inhibitors may be promising treatments, in combination with irbesartan, for DN with hypertension as they demonstrate complementary mechanisms.

Abstract P228: Mineralocorticoid Receptor Antagonist And Lipophilic Statin Reduce Urinary Kidney Injury Marker 1 (Kim-1) In Female Rats Receiving L-NAME And Angiotensin II

Statins have beneficial cardiovascular effects some of which appear to be cholesterol-independent and the mechanisms for these latter effects are still unclear. Urinary kidney injury molecule-1 (Kim-1) is a sensitive biomarker of acute renal injury and in clinical studies predicts cardiovascular disease. Aldosterone causes both cardiac and renal injury and a few studies suggest that aldosterone is associated with increased Kim-1. Therefore, in this study we used the N omega-nitro-L-arginine methyl ester (L-NAME)/Angiotensin II (AngII) model of cardiorenal injury to determine whether urinary Kim-1 correlates with the degree of cardiac injury/stroke and whether blockade of the mineralocorticoid receptor prevents increases in urinary Kim-1. Further, since our group reported previously that lipophilic statins, but not hydrophilic statins reduce aldosterone levels, we also asked whether administration of either a lipophilic or a hydrophilic statin affects Kim-1 levels. To test the hypothesis, 8-10 week-old, female Wistar rats consuming liberal salt diet (1.6% Na + ) were randomized to the following conditions for 14 days: control; L-NAME (0.2 mg/ml in drinking water)/AngII (225ug/kg/day for days 12-14 only); L-NAME/AngII + eplerenone (100 mg/kg/day p.o.); L-NAME/Ang II + pravastatin (hydrophilic statin-20 mg/kg/day p.o.); L-NAME/Ang II + simvastatin (lipophilic statin-20 mg/kg/day p.o.) groups. Groups treated with L-NAME/AngII had significantly higher blood pressure, urine aldosterone and plasma aldosterone levels compared to control. L-NAME/AngII treatment increased cardiac injury/stroke composite score, including cardiac histopathology evaluation and stroke status, and 24 hour-urinary Kim-1 compared to control. Eplerenone reduced cardiac injury/stroke composite score (p=0.04) and both eplerenone and simvastatin reduced urinary Kim-1 (p=0.0046, p=0.031, respectively). Pravastatin had no effect on these damage markers. Urinary Kim-1 correlated with cardiac injury/stroke composite score (p&lt;0.0001, spearman ranked correlation=0.67). In conclusion, in a rat model of L-NAME/AngII induced cardiovascular injury, urinary Kim-1 predicts cardiac/stroke injury; eplerenone and simvastatin reduced urinary Kim-1.

(Pro)renin receptor decoy peptide PRO20 protects against adriamycin-induced nephropathy by targeting the intrarenal renin-angiotensin system.

Adriamycin (ADR) administration in susceptible rodents such as the BALB/c mouse strain produces injury to the glomerulus mimicking human chronic kidney disease due to primary focal segmental glomerulosclerosis. The goal of the present study was to use this model to investigate antiproteinuric actions of the (pro)renin receptor decoy inhibitor PRO20. BALB/c mice were pretreated for 1 day with PRO20 at 500 μg·kg-1·day-1 via an osmotic minipump followed by a single injection of vehicle or ADR (10 mg/kg) via the tail vein. Albuminuria and renal function were analyzed at the fourth week post-ADR administration. ADR-treated mice exhibited severe proteinuria, hypoalbuminemia and hyperlipidemia, glomerulosclerosis, podocyte loss, tubulointerstitial fibrosis, and oxidative stress, accompanied by elevated urinary neutrophil gelatinase-associated lipocalin and kidney injury molecule-1, all of which were significantly attenuated by PRO20. Urinary and renal renin activity and angiotensin II were elevated by ADR and suppressed by PRO20. In parallel, urinary and renal H2O2 levels and renal NADPH oxidase 4 (Nox4) and transient receptor potential channel C6 (TRPC6) expression in response to ADR were all similarly suppressed. Taken together, the results of the present study provide the first evidence that PRO20 can protect against podocyte damage and interstitial fibrosis in ADR nephropathy by preventing activation of the intrarenal renin-angiotensin system and upregulation of Nox4 and TRPC6 expression. PRO20 may have a potential application in the treatment of ADR nephropathy.

Role of urinary NGAL and KIM-1 as biomarkers of early kidney injury in obese prepubertal children.

Objectives Childhood obesity is an important cause of end-stage renal disease. To date, available markers do not characterize kidney changes, especially in the early stages. kidney injury molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) are already detected before the onset of proteinuria or alterations of glomerular filtration rate and thus might represent biomarkers that directly reflect kidney injury. Methods We characterize kidney injury in a group of 40 obese-prepubertal children compared to 29-healthy age- and gender matched-peers. Anthropometric measurements and body composition were determined. Fasting blood samples were collected for measurement of insulin, glucose, lipid profile, transaminases, cystatin C and creatinine. Urine samples were collected to assess urinary NGAL, KIM-1 and urinary isoprostanes. Kidney length was measured with ultrasound evaluation. Differences between the two groups were evaluated by Mann-Whitney U test, and Spearman correlation analysis was used to explore relationship between variables. Results Triglycerides, alanine transaminase (ALT), glucose, insulin, homeostasis model assessment insulin resistance, triglycerides/high-density lipoprotein (HDL)-cholesterol ratio and cystatin C values were significantly higher in obese children than normal weight peers. Creatinine values were normal and similar between the two groups, while isoprostanes were higher in obese. Obese children had larger kidney sizes, indicating organ hypertrophy. NGAL and KIM-1 were increased in obese children compared to controls. A significant association between NGAL and KIM-1 with adiposity indices, insulin status and markers of oxidative stress postulated a possible effect of obesity in inducing kidney abnormalities. KIM-1 and NGAL are directly related respectively to cystatin C and isoprostanes, supporting the ability of these biomarkers in reflecting early kidney damages in obese subjects. Conclusions These findings suggest that obese subjects exhibit a certain degree of renal damage before kidney function loss.

Effects of Angiotensin-Neprilysin Inhibition in Canines with Experimentally Induced Cardiorenal Syndrome

BackgroundSacubitril/valsartan (Sac/Val), a combined angiotensin-II receptor blocker (Val) and neprilysin inhibitor (Sac) in a 1:1 molar ratio, was shown to decrease the risk of cardiovascular death or heart failure (HF) hospitalization in patients with HF and reduced left ventricular (LV) ejection fraction. This study examined the effects of Sac/Val on LV structure, function, and bioenergetics, and on biomarkers of kidney injury and kidney function in dogs with experimental cardiorenal syndrome. Methods and ResultsFourteen dogs with cardiorenal syndrome (coronary microembolization-induced HF and renal dysfunction) were randomized to 3 months Sac/Val therapy (100 mg once daily, n = 7) or no therapy (control, n = 7). LV ejection fraction and troponin-I, as well as biomarkers of kidney injury/function including serum creatinine and urinary kidney injury molecule-1 were measured before and at end of therapy and the change (treatment effect change) calculated. Mitochondrial function measures, including the maximum rate of adenosine triphosphate synthesis, were measured in isolated cardiomyocytes at end of therapy. In Sac/Val dogs, the change in ejection fraction increased compared with controls, 6.9 ± 1.4 vs 0.7 ± 0.6%, P < .002, whereas change in troponin I decreased, –0.16 ± 0.03 vs –0.03 ± 0.02 ng/mL, P < .001. Urinary change in kidney injury molecule 1 decreased in Sac/Val–treated dogs compared with controls, –17.2 ± 7.9 vs 7.7 ± 3.0 mg/mL, P < .007, whereas the change in serum creatinine was not significantly different. Treatment with Sac/Val increased adenosine triphosphate synthesis compared with controls, 3240 ± 121 vs 986 ± 84 RLU/µg protein, P < .05. ConclusionsIn dogs with cardiorenal syndrome, Sac/Val improves LV systolic function, improves mitochondrial function and decreases biomarkers of heart and kidney injury. The results offer mechanistic insights into the benefits of Sac/Val in HF with compromised renal function.

The Predictive Value of Urinary Kidney Injury Molecular 1 for the Diagnosis of Contrast-Induced Acute Kidney Injury after Cardiac Catheterization: A Meta-Analysis.

Background Urinary kidney injury molecule 1 (uKIM-1) is a proximal tubular injury biomarker for predicting acute kidney injury (AKI); its prognostic value varies depending on the clinical and population characteristics. However, the predictive value of uKIM-1 for diagnosis of contrast-induced acute kidney injury (CI-AKI) remains unclear. Method Medline, Embase, ClinicalTrials.gov, Cochrane Library database, and the China National Knowledge Infrastructure (CNKI) were used to identify relevant studies from their inception to November 31, 2019. Studies that met the inclusion criteria were included. Relevant data were extracted to obtain pooled sensitivity (SEN) and specificity (SPE), summary receiver operating characteristic curve (ROC), and area under the ROC (AUC or AUROC). A bivariate mixed-effects regression model was used for data analysis. Results A total of 946 patients from 8 eligible studies were included. Across all the studies, the diagnostic odds ratio (DOR) for uKIM-1 level to predict CI-AKI was 19 (95% CI 10–39), with SEN and SPE of 0.84 and 0.78, respectively. The AUROC for uKIM-1 in predicting CI-AKI was 0.88 (95% CI 0.85–0.90). There was a substantial heterogeneity across the studies (I2 was 37.73% for the summary sensitivity and 69.31% for the summary specificity). Conclusion Urinary KIM-1 has a high predictive value for diagnosis of CI-AKI in patients who have undergone cardiac catheterization.

AdipoRon, an adiponectin receptor agonist, protects contrast-induced nephropathy by suppressing oxidative stress and inflammation via activation of the AMPK pathway.

Contrast-induced nephropathy (CIN), a complication caused by using contrast medium during diagnostic and interventional procedures, occurs frequently and lacks effective treatment. AdipoRon, the agonist of adiponectin receptors, has been shown to benefit many organs including the kidney. This study aimed to investigate the role of AdipoRon in treating CIN. CIN model was established via infusing iopromide (1.8g/kg) in Sprague-Dawley (SD) rats; NRK52E cells were treated with iopromide (5-50μM). Renal function, renal histopathology, levels of lactate dehydrogenase (LDH) release, cell vitality, oxidative stress and inflammatory markers were measured to evaluate the protective effects of AdipoRon. The level of pAMPK/AMPK was determined by western blot. AdipoRon (50mg/kg) significantly reversed serum creatinine, blood urea nitrogen, creatinine clearance and urinary kidney injury molecule-1 levels induced by iopromide in SD rats. Besides, it decreased the renal injury score and apoptosis of renal cells. AdipoRon also reversed the changes of antioxidant markers, pro-oxidant and inflammatory markers induced by iopromide. Moreover, the in vitro studies showed that AdipoRon decreased LDH release and increased cell vitality in NRK52E cells treated with iopromide. Then, we demonstrated that the protection of AdipoRon was accompanied by augmented AMPK phosphorylation. Both in vivo and in vitro studies demonstrated that compound c, an AMPK inhibitor, reversed the AdipoRon-mediated improvement in the CIN model. Our data indicate that AdipoRon protects against the CIN by suppressing oxidative stress and inflammation via activating the AMPK pathway, showing that AdipoRon might be a potential candidate for the prevention and therapy of CIN.

Association of TNF-α-308 (G >A) (rs1800629) Gene Polymorphism with Adverse Outcomes of Sepsis in Critically Ill Patients.

Sepsis-related mortality and morbidity are major health care problems worldwide. More effort is required to identify factors associated with adverse outcome. Evaluate the prognostic capacity of tumor necrosis factor (TNF), kidney injury molecule (KIM), and lactate and TNF-α-308 G > A gene polymorphism for prediction of 28 days-intensive care unit (ICU) mortality. TNF-α-308 G > A single nucleotide polymorphisms was detected by real-time-PCR on 112 had septic shock and 88 were septic. Serum TNF-α and urinary KIM were assessed by enzyme-linked immunosorbent assay. This study included 200 critically ill patients, 125 (62.5%) of them died within 28 days in ICU (nonsurvivors). Frequencies of TNF-308 G > A was (70.7) GG, (28) GA and (1.3) AA in survivors versus (85.6) GG, (12) GA and (2.4) AA for nonsurvivors, revealed significant association with ICU mortality but not sepsis severity (p = 0.15) or sepsis-induced acute kidney injury (AKI). In contrast, urinary KIM-1 revealed significant association with sepsis severity (p = 0.036) and AKI (p = 0.0001), but not 28-days ICU mortality. The relative risk of death in patients with GG genotype was 2.5 mainly in ICU younger male patients (odds ratios 24 and 4.9, p = 0.001). The genotype GG and GA were significantly associated with [increased urinary KIM-1 (0.29 ± 0.1) (p = 0.0001), terminal creatinine (1.67 ± 0.8) (p = 0.0001)] and [increased terminal urea (109 ± 0.001) (p = 0.001) and basal serum TNF (60 ± 0.001) (p = 0.0001)], respectively. In linear regression analysis, AKI 0.0001 (0.4-0.67), basal serum TNF 0.04 (0.0001-0.04), and TNF-308 GG 0.007 (0.05-0.33) were associated with 28 days ICU mortality [p value (95% confidence interval)]. The same results were observed for initial urea 0.024 (0.0001-0.003) and lack of diuretic usage 0.0001 (0.35-0.7) mainly in septic patients. Major frequency of TNF-308 G > A polymorphism (mainly in young age male patients), AKI and serum TNF were associated with increased risk for 28 days-ICU mortality. Furthermore, sepsis severity was influenced by TNF and urinary KIM-1, which reflects in AKI.