KIM-1、CC16在急性肾/肺损伤临床诊断中的意义

目的观察肾损伤分子-1（kidney injury molecule 1, KIM-1）与Clara细胞分泌蛋白（Clara cell secretion protein, CCSP/CC16）在急性肾损伤（Acute Kidney Injury, AKI）合并急性肺损伤（Acute Lung Injury, ALI）患者体内的变化,探讨其在急性肾/肺损伤临床诊断中的意义。方法入选本院确诊为AKI的患者纳入AKI组（25例）,确诊为ALI的患者纳入ALI组（15例）,确诊为AKI合并ALI的患者纳入AKI+ALI组（25例）,与之年龄、性别、民族相匹配的非吸烟健康志愿者作为正常对照组（23例）,采用酶联免疫吸附法(enzyme-linked immunosorbent assay, ELISA)检测尿液KIM-1、尿液CC16和血浆KIM-1、血浆CC16的水平,用比色法检测尿N-乙酰-β-D-氨基葡萄糖苷酶(N-acetyl-beta-D-glucosaminidase, NAG),整理四组所有研究资料利用统计学方法进行综合分析。 结果与正常非吸烟对照组相比,AKI组的尿NAG酶、尿KIM-1、血浆KIM-1和血浆CC16水平均显著升高,差异有统计学意义（P＜0.05）;ALI组的尿CC16和血浆CC16水平均显著升高,差异有统计学意义（P＜0.05）;AKI+ALI组的尿NAG酶、尿KIM-1、血浆KIM-1、尿CC16和血浆CC16水平均显著升高,差异有统计学意义（P＜0.05）。 直线相关分析显示：AKI患者的尿KIM-1水平与尿NAG呈显著正相关关系（r=0.493, P＜0.01）,血浆KIM-1水平与尿NAG无直线相关关系（r=0.276, P＞0.05）。ALI患者的尿CC16、血浆CC16与氧合指数均呈显著负相关关系(r=0.460, P＜0.01; r=0.468, P＜0.01)。AKI合并ALI患者的尿KIM-1、血浆KIM-1与尿CC16、血浆CC16均呈显著正相关关系（P＜0.05）。3. ROC曲线分析提示：在AKI诊断中,尿KIM-1曲线下面积为0.781（95% CI：0.688～0.875,P＜0.01）;血浆KIM-1曲线下面积为0.988（95% CI：0.000～1.000,P＜0.01）;尿NAG酶曲线下面积为0.798（95% CI：0.708～0.888,P＜0.01）。在ALI诊断中,尿CC16曲线下面积为1.000(95% CI：1.000～1.000,P＜0.01);血浆CC16曲线面积为0.849（95% CI：0.764～0.935,P＜0.01）。 结论 AKI时尿NAG、尿KIM-1、血浆KIM-1均明显升高,进一步证实这些指标可作为诊断AKI早期生物学标志物。2. ALI时尿CC16、血浆CC16水平显著升高,同时具有高敏感性,是诊断ALI的良好实验室指标。急性肾/肺损伤患者体内尿、血浆KIM-1与CC16水平明显升高,二者具有良好的相关性,对诊断急性肾/肺损伤并判断预后具有重要的价值与临床意义。     

尿NGAL、NAG及KIM-1联合检测在高龄老年急性肾损伤早期诊断中的价值

目的探讨尿中性粒细胞明胶酶相关脂质运载蛋白(uNGAL)、尿N-乙酰β-D氨基葡萄糖苷酶(uNAG)及尿肾损伤分子-1(uKIM-1)的联合检测老年急性肾损伤中的诊断价值。方法选择2016年6月至2018年6月在泰山疗养院住院的老年患者184例,根据急性肾损伤网络(AKIN)标准为诊断标准,诊断AKI组116例(1期55例、2期39例、3期24例),非AKI组68例,检测并比较各组尿NGAL、NAG、KIM-1水平,用受试者工作特征曲线(ROC)及曲线下面积(AUC)分析3项生物学标志物对AIK的诊断价值。结果①AKI组尿NGAL、NAG、KIM-1明显高于对照组(P<0.05),3期尿NGAL、NAG、KIM-1明显高于2期和1期,2期明显高于1期(P<0.05);②尿NGAL、NAG、KIM-1单独诊断AKI的AUC分别为0.734、0.804、0.705;③3项标志物联合诊断AKI的灵敏度、特异度分别为84.9%、90.7%,高于各单项诊断。结论尿NGAL、NAG、KIM-1是诊断AKI的较好指标,联合诊断对高龄老年急性肾损伤的早期诊断有着更重要的价值。     

Prognostic value of urinary kidney injury molecule 1, interleukin 18 and cystatin C as biomarkers for gadolinium-based contrast-induced nephropathy in the elderly patients

Objective To assess the prognostic values of urinary kidney injury molecule 1 (KIM-1), interleukin 18 (IL-18) and cystatin C (Cys C) for gadolinium-based contrast-induced nephropathy (Gd-CIN) in the elderly patients. Methods A total of sixty elderly patients who underwent enhanced magnetic resonance imaging (MRI) using gadolinium-based contrast media (GBC) from December 2010 to December 2011 were enrolled. Serum and urine samples were collected before and after the procedure. The levels of urinary KIM-1, IL-18 and Cys C were measured by ELISA respectively. Serum and urine creatinine levels were measured by automatic biochemical analyzer. Results Among 60 patients, Gd-CIN was diagnosed in 8 (13.3%) patients. At 24 h after MRI in the Gd-CIN group, the levels of urinary KIM-1, IL-18 and Cys C were significantly increased compared with the baseline values. Compared with non-Gd-CIN group, the levels of urinary KIM-1, IL-18 and Cys C at 24 h and urinary IL-18 at 48 h after GBC administration were significantly increased (P＜0.05). There were no significant differences in levels of urinary KIM-1, Cys C at 48 h after GBC administration between Gd-CIN and non-Gd-CIN group (P＞0.05). Logistic regression analysis showed that the levels of urinary KIM-1 and IL-18 at 24 h after GBC injection were independent predictive biomarkers of Gd-CIN (OR＝1.612, 1.009, all P＜0.05). The predictable time of acute kidney injury onset determined by urinary KIM-1, IL-18 and Cys C levels was 24 h earlier than that by serum creatinine. Conclusion Urinary KIM-1, IL-18 and Cys C may be early predictive biomarkers of elderly Gd-CIN, which shows a good performance in early diagnosis of Gd-CIN as compared with serum creatinine.     

Kidney injury molecule-1 correlates with kidney function in renal allograft recipients

IntroductionKIM-1 (kidney injury molecule-1) is responsible for the clearance of debris from damaged renal tubules. KIM-1 can be expressed and excreted in urine within 12 hours after the initial ischemic insult and before regeneration of the epithelium, persisting over time thereafter. Urinary KIM-1 has been reported to be a noninvasive, rapid, sensitive, and reproducible biomarker of experimental nephrotoxic and ischemic acute kidney injury. Renal KIM-1 expression is significantly increased in human kidney tissue among patients with a wide range of kidney diseases, including various types of glomerulonephritis, chronic allograft nephropathy, acute rejection, hypertension, and Wegener's granulomatosis. Both renal and urinary KIM-1 correlate with kidney damage and negatively with renal function, but not with proteinuria. The aim of this study was to assess whether urinary KIM-1 correlated with kidney function in kidney allograft recipients.MethodsSerum NGAL, creatinine and estimated glomerular filtration rate (eGFR) were evaluated in 170 kidney allograft recipients on therapy with a calcineurin inhibitor plus mycophenolate mofetil or azathioprine and prednisone as well as in healthy volunteers. KIM-1 was estimated in urine using a commercially available kit.ResultsKidney transplant recipients showed significantly higher KIM-1 values than the control group. Normotensive kidney allograft recipients displayed significantly lower NGAL results than hypertensive subjects. Urinary KIM-1 was significantly higher among diabetic than nondiabetic subjects, whereas creatinine did not differ significantly between them. Upon univariate analysis urinary KIM-1 strongly correlated with serum creatinine (r = .64) and eGFR (r = ?.71), and only weakly with other parameters. Upon multiple regression analysis, the best predictor of urinary KIM-1 was eGFR (beta ?0.61), which explained 61% of KIM-1 concentrations.ConclusionEven a successful kidney transplantation is associated with kidney injury as reflected by elevated urinary KIM-1 and lower eGFR. Therefore, KIM-1 needs to be investigated as a potential early marker for impaired renal function/kidney injury, especially in patients with other risk factors for damage such as hypertension or diabetes.     

Urinary N-acetyl-beta-(D)-glucosaminidase activity and kidney injury molecule-1 level are associated with adverse outcomes in acute renal failure

The role of urinary biomarkers of kidney injury in the prediction of adverse clinical outcomes in acute renal failure (ARF) has not been well described. The relationship between urinary N-acetyl-beta-(D)-glucosaminidase activity (NAG) and kidney injury molecule-1 (KIM-1) level and adverse clinical outcomes was evaluated prospectively in a cohort of 201 hospitalized patients with ARF. NAG was measured by spectrophotometry, and KIM-1 was measured by a microsphere-based Luminex technology. Mean Acute Physiology, Age, Chronic Health Evaluation II (APACHE II) score was 16, 43% had sepsis, 39% required dialysis, and hospital mortality was 24%. Urinary NAG and KIM-1 increased in tandem with APACHE II and Multiple Organ Failure scores. Compared with patients in the lowest quartile of NAG, the second, third, and fourth quartile groups had 3.0-fold (95% confidence interval [CI] 1.3 to 7.2), 3.7-fold (95% CI 1.6 to 8.8), and 9.1-fold (95% CI 3.7 to 22.7) higher odds, respectively, for dialysis requirement or hospital death (P < 0.001). This association persisted after adjustment for APACHE II, Multiple Organ Failure score, or the combined covariates cirrhosis, sepsis, oliguria, and mechanical ventilation. Compared with patients in the lowest quartile of KIM-1, the second, third, and fourth quartile groups had 1.4-fold (95% CI 0.6 to 3.0), 1.4-fold (95% CI 0.6 to 3.0), and 3.2-fold (95% CI 1.4 to 7.4) higher odds, respectively, for dialysis requirement or hospital death (P = 0.034). NAG or KIM-1 in combination with the covariates cirrhosis, sepsis, oliguria, and mechanical ventilation yielded an area under the receiver operator characteristic curve of 0.78 (95% CI 0.71 to 0.84) in predicting the composite outcome. Urinary markers of kidney injury such as NAG and KIM-1 can predict adverse clinical outcomes in patients with ARF.     

Kidney injury molecule-1 as a biomarker of acute kidney injury in renal transplant recipients

This Practice Point commentary discusses a study by Zhang and colleagues that investigated the usefulness of kidney injury molecule-1 (KIM-1) for the early diagnosis of tubular injury on renal biopsy. The study found that KIM-1 protein expression was present in 100% of biopsies that showed acute tubular injury, and in 28% of protocol kidney biopsies that showed no morphological pathology. KIM-1 levels showed positive correlation with serum creatinine and blood urea nitrogen levels, and inverse correlation with estimated glomerular filtration rate. We discuss the findings of Zhang et al., and describe other potential biomarkers for detecting early tubular injury that are currently under investigation. KIM-1, potentially in combination with other biomarkers, might be useful for diagnosing early acute tubular injury on renal biopsy, and might also be of prognostic significance.     

Urinary Biomarkers of AKI and Mortality 3 Years after Cardiac Surgery

Urinary biomarkers of AKI provide prognostic value for in-hospital outcomes, but little is known about their association with longer-term mortality after surgery. We sought to assess the association between kidney injury biomarkers and all-cause mortality in an international, multicenter, prospective long-term follow-up study from six clinical centers in the United States and Canada composed of 1199 adults who underwent cardiac surgery between 2007 and 2009 and were enrolled in the Translational Research in Biomarker Endpoints in AKI cohort. On postoperative days 1–3, we measured the following five urinary biomarkers: neutrophil gelatinase-associated lipocalin, IL-18, kidney injury molecule-1 (KIM-1), liver fatty acid binding protein, and albumin. During a median follow-up of 3.0 years (interquartile range, 2.2–3.6 years), 139 participants died (55 deaths per 1000 person-years). Among patients with clinical AKI, the highest tertiles of peak urinary neutrophil gelatinase-associated lipocalin, IL-18, KIM-1, liver fatty acid binding protein, and albumin associated independently with a 2.0- to 3.2-fold increased risk for mortality compared with the lowest tertiles. In patients without clinical AKI, the highest tertiles of peak IL-18 and KIM-1 also associated independently with long-term mortality (adjusted hazard ratios [95% confidence intervals] of 1.2 [1.0 to 1.5] and 1.8 [1.4 to 2.3] for IL-18 and KIM-1, respectively), and yielded continuous net reclassification improvements of 0.26 and 0.37, respectively, for the prediction of 3-year mortality. In conclusion, urinary biomarkers of kidney injury, particularly IL-18 and KIM-1, in the immediate postoperative period provide additional prognostic information for 3-year mortality risk in patients with and without clinical AKI.In many studies, the development of AKI, defined by acute changes in serum creatinine, associates with a higher risk of long-term mortality.^1,2 Acute changes in serum creatinine, however, may not fully reflect the severity of kidney injury due to the influence of age, sex, muscle mass, changes in hydration, nutritional status, and medications on creatinine kinetics. Moreover, serum creatinine may abruptly rise in hospitalized settings due to functional processes such as altered hemodynamics, without any true nephron damage. Several urinary biomarkers of structural kidney injury have been investigated in human cohorts in an effort to identify AKI earlier, improve the diagnosis of AKI, and to aid in risk stratification.³ It is largely unknown, however, whether kidney injury biomarkers associate with long-term outcomes, including mortality, and whether these biomarkers add useful prognostic information beyond the standard measure to detect AKI (e.g., peak change in serum creatinine). Some data suggest that “subclinical AKI,” as evidenced by elevations in urinary kidney injury biomarkers in the absence of a rise in serum creatinine, associates with worse in-hospital clinical outcomes.⁴ Few studies have examined whether kidney injury biomarkers associate with long-term mortality after hospital discharge.⁵To address the current knowledge gaps, we conducted this study to characterize the association between kidney injury biomarkers and long-term mortality and to assess whether these biomarkers provide any incremental prognostic information for long-term mortality beyond that of serum creatinine changes and other clinical variables.     

Blood Kidney Injury Molecule-1 Is a Biomarker of Acute and Chronic Kidney Injury and Predicts Progression to ESRD in Type I Diabetes

Currently, no blood biomarker that specifically indicates injury to the proximal tubule of the kidney has been identified. Kidney injury molecule-1 (KIM-1) is highly upregulated in proximal tubular cells following kidney injury. The ectodomain of KIM-1 is shed into the lumen, and serves as a urinary biomarker of kidney injury. We report that shed KIM-1 also serves as a blood biomarker of kidney injury. Sensitive assays to measure plasma and serum KIM-1 in mice, rats, and humans were developed and validated in the current study. Plasma KIM-1 levels increased with increasing periods of ischemia (10, 20, or 30 minutes) in mice, as early as 3 hours after reperfusion; after unilateral ureteral obstruction (day 7) in mice; and after gentamicin treatment (50 or 200 mg/kg for 10 days) in rats. In humans, plasma KIM-1 levels were higher in patients with AKI than in healthy controls or post-cardiac surgery patients without AKI (area under the curve, 0.96). In patients undergoing cardiopulmonary bypass, plasma KIM-1 levels increased within 2 days after surgery only in patients who developed AKI (P<0.01). Blood KIM-1 levels were also elevated in patients with CKD of varous etiologies. In a cohort of patients with type 1 diabetes and proteinuria, serum KIM-1 level at baseline strongly predicted rate of eGFR loss and risk of ESRD during 5–15 years of follow-up, after adjustment for baseline urinary albumin-to-creatinine ratio, eGFR, and Hb1Ac. These results identify KIM-1 as a blood biomarker that specifically reflects acute and chronic kidney injury.     

Kidney injury molecule-1 expression in transplant biopsies is a sensitive measure of cell injury

Kidney injury molecule-1 (KIM-1) is a specific histological biomarker for diagnosing early tubular injury on renal biopsies. In this study, KIM-1 expression was quantitated in renal transplant biopsies by immunohistochemistry and correlated with renal function. None of the 25 protocol biopsies showed detectable tubular injury on histologic examination, yet 28% had focal positive KIM-1 expression. Proximal tubule KIM-1 expression was present in all biopsies from patients with histological changes showing acute tubular damage and deterioration of kidney function. In this group, higher KIM-1 staining predicted a better outcome with improved blood urea nitrogen (BUN), serum creatinine, and estimated glomerular filtration rate (eGFR) over an ensuing 18 months. KIM-1 was expressed focally in affected tubules in 92% of kidney biopsies from patients with acute cellular rejection. By contrast, there was little positive staining for Ki-67, a cell proliferation marker, in any of the groups. KIM-1 expression significantly correlated with serum creatinine and BUN, and inversely with the eGFR on the biopsy day. Our study shows that KIM-1 staining sensitively and specifically identified proximal tubular injury and correlated with the degree of renal dysfunction. KIM-1 expression is more sensitive than histology for detecting early tubular injury, and its level of expression in transplant biopsies may indicate the potential for recovery of kidney function.     

Value of joint detection of multiple biomarkers on early diagnosis of acute kidney injury in critical patients

Objective To assess the value of joint detection of serum cysteine proteinase inhibitors C (sCys-C), urinary kidney injury molecule 1 (uKIM-1), urinary neutrophil gelatinase-associated lipocalin(uNGAL) and urinary interleukin 18 (uIL-18) for early diagnosis of acute kidney injury (AKI) in critically ill patients. Methods A total of 256 adult patients who stayed Intensive Care Unit for 24 hours in the Third People's Hospital of Liaocheng between Aug 2011 and Dec 2012 were enrolled. According to Kidney Injury Net(AKIN) work, the patients were divided into non-AKI group and AKI group (including state 1, 2 and 3). The concentrations of urine NGAL, KIM-1, IL-18 and serum sCys-C were measured. The diagnosis value of four biomarkers joint detection and single detection for AKI were analyzed with the receiver operating characteristic (ROC) curve and the area under curve (AUC). Results (1) The levels of uNGAL, uKIM-1, uIL-18 and sCys-C were higher in patients with AKI than the patients with no AKI (P﹤0.01). (2) The area under curves of uNGAL, uKIM-1, uIL-18, sCys-C and joint detection were 0.742, 0.871, 0.803, 0.703, 0.925 respectively. (3) The sensitivity and specificity of parallel tests and serial tests of four biomarkers were 97.9%, 62.8%, 64.3% and 96.2% respectively. There were significant differences of sensitivity or specificity between single test and joint tests. Conclusions The urine NGAL, KIM-1, IL-18 and serum Cys-C are sensitive indexes for the early diagnosis of acute kidney injury. Joint detection has high value for early diagnosis of AKI.     

Biomarkers for the diagnosis and risk stratification of acute kidney injury: a systematic review

The diagnosis of acute kidney injury (AKI) is usually based on changes in serum creatinine, but such measurements are a poor marker of acute deterioration in kidney function. We performed a systematic review of publications that evaluated the accuracy and reliability of serum and urinary biomarkers in human subjects when used for the diagnosis of established AKI or early AKI, or to risk stratify patients with AKI. Two reviewers independently searched the MEDLINE and EMBASE databases (January 2000-March 2007) for studies pertaining to biomarkers for AKI. Studies were assessed for methodologic quality. In total, 31 studies evaluated 21 unique serum and urine biomarkers. Twenty-five of the 31 studies were scored as having 'good' quality. The results of the studies indicated that serum cystatin C, urine interleukin-18 (IL-18), and urine kidney injury molecule-1 (KIM-1) performed best for the differential diagnosis of established AKI. Serum cystatin C and urine neutrophil gelatinase-associated lipocalin, IL-18, glutathione-S-transferase-pi, and gamma-glutathione-S-transferase performed best for early diagnosis of AKI. Urine N-acetyl-beta-D-glucosaminidase, KIM-1, and IL-18 performed the best for mortality risk prediction after AKI. In conclusion, published data from studies of serum and urinary biomarkers suggest that biomarkers may have great potential to advance the fields of nephrology and critical care. These biomarkers need validation in larger studies, and the generalizability of biomarkers to different types of AKI as well as the incremental prognostic value over traditional clinical variables needs to be determined.     

Regression of microalbuminuria in type 1 diabetes is associated with lower levels of urinary tubular injury biomarkers, kidney injury molecule-1, and N-acetyl-β-D-glucosaminidase

Elevated urinary albumin excretion in patients with type 1 diabetes reverts to normoalbuminuria in a majority of patients but advances toward proteinuria in some. In order to gain valuable insights into the early pathophysiology of diabetic nephropathy we evaluated the association of kidney tubular injury biomarkers with changes in albuminuria in patients with type 1 diabetes mellitus. Urine levels of kidney injury molecule-1 (KIM-1), N-acetyl-β-D-glucosaminidase (NAG), and some inflammatory markers were determined in 38 healthy individuals and 659 patients with type 1 diabetes mellitus having varying degrees of albuminuria. Urinary interleukin-6, CXCL10/IP-10, NAG, and KIM-1 levels were very low in healthy individuals, increased in type 1 patients with normoalbuminuria, and were highest in diabetic patients that had microalbuminuria. Low baseline concentrations of urinary KIM-1 and NAG both individually and collectively were significantly associated with the regression of microalbuminuria over the subsequent 2 years; an effect independent of clinical characteristics. Progression and regression of microalbuminuria were unrelated to urinary levels of interleukins 6 and 8, CXCL10/IP-10, and monocyte chemoattractant protein-1. Thus our results show that lower urinary KIM-1 and NAG levels were associated with the regression of microalbuminuria in type 1 diabetes mellitus. Hence, tubular dysfunction is a critical component of the early course of diabetic nephropathy.     

Kidney injury molecule-1 correlates with kidney function in heart allograft recipients

Serum creatinine and estimated glomerular filtration rate (eGFR) (24 hours creatinine clearance, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, Cockcroft-Gault formulae), and urinary kidney injury molecule-1 (KIM-1), were evaluated in 111 heart allograft recipients on therapy with a calcineurin inhibitor, mycophenolate mofetil or azathioprine plus prednisone. KIM-1 was assessed using commercially available assay. Normotensive heart allograft recipients showed significantly lower KIM-1 values than hypertensive subjects. Urinary KIM-1 was significantly higher among New York Heart Association class III versus I and II patients. Upon univariate analysis, urinary KIM-1 strongly correlated with serum creatinine (r = .54) and eGFR (r = .66) but only weakly with other parameters. It was not related to cystatin C. Upon multiple regression analysis, the best predictor of urinary KIM-1 was eGFR (beta −0.56), explaining 76% of KIM-1 concentrations. Even a successful heart transplantation is associated with kidney injury as reflected by elevated urinary KIM-1 and reduced eGFR. Therefore, KIM-1 needs to be investigated as a potential early marker for impaired kidney function/kidney injury, especially in patients with other risk factor for kidney damage, for example, hypertension or congestive heart failure.     

Effect of renin-angiotensin-aldosterone system inhibition, dietary sodium restriction, and/or diuretics on urinary kidney injury molecule 1 excretion in nondiabetic proteinuric kidney disease: a post hoc analysis of a randomized controlled trial

BACKGROUND: Tubulointerstitial damage plays an important role in chronic kidney disease (CKD) with proteinuria. Urinary kidney injury molecule 1 (KIM-1) reflects tubular KIM-1 and is considered a sensitive biomarker for early tubular damage. We hypothesized that a decrease in proteinuria by using therapeutic interventions is associated with decreased urinary KIM-1 levels. STUDY DESIGN: Post hoc analysis of a randomized, double-blind, placebo-controlled, crossover trial. SETTING & PARTICIPANTS: 34 proteinuric patients without diabetes from our outpatient renal clinic. INTERVENTION: Stepwise 6-week interventions of losartan, sodium restriction (low-sodium [LS] diet), their combination, losartan plus hydrochlorothiazide (HCT), and the latter plus an LS diet. OUTCOMES & MEASUREMENTS: Urinary excretion of KIM-1, total protein, and N-acetyl-beta-d-glucosaminidase (NAG) as a positive control for tubular injury. RESULTS: Mean baseline urine protein level was 3.8 +/- 0.4 (SE) g/d, and KIM-1 level was 1,706 +/- 498 ng/d (increased compared with healthy controls; 74 ng/d). KIM-1 level was decreased by using placebo/LS (1,201 +/- 388 ng/d; P = 0.04), losartan/high sodium (1,184 +/- 296 ng/d; P = 0.09), losartan/LS (921 +/- 176 ng/d; P = 0.008), losartan/high sodium plus HCT (862 +/- 151 ng/d; P = 0.008) and losartan/LS plus HCT (743 +/- 170 ng/d; P = 0.001). The decrease in urinary KIM-1 levels paralleled the decrease in proteinuria (R = 0.523; P < 0.001), but not blood pressure or creatinine clearance. 16 patients reached target proteinuria with protein less than 1 g/d, whereas KIM-1 levels normalized in only 2 patients. Urinary NAG level was increased at baseline and significantly decreased during the treatment periods of combined losartan plus HCT only. The decrease in urinary NAG levels was not closely related to proteinuria. LIMITATIONS: Post hoc analysis. CONCLUSIONS: Urinary KIM-1 level was increased in patients with nondiabetic CKD with proteinuria and decreased in parallel with proteinuria by using losartan, sodium restriction, their combination, losartan plus HCT, and the latter plus sodium restriction. These results are consistent with the hypothesis of amelioration of proteinuria-induced tubular damage. Long-term studies are warranted to evaluate whether targeting treatment on KIM-1 can improve outcomes in patients with CKD with proteinuria.     

Urinary and Serum Biomarkers after Cardiac Catheterization in Diabetic Patients with Stable Angina and without Severe Chronic Kidney Disease

Background/Aims. Different serum and urinary biomarkers have been recently proposed to serve as markers of acute kidney injury. We tested the hypothesis whether NGAL and other biomarkers could represent an early biomarker of contrast nephropathy (CIN) in diabetic patients with normal serum creatinine undergoing cardiac catheterization in comparison with non-diabetic patients. Methods. Serum, urinary NGAL, cystatin C, urinary kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), and liver-type fatty acid binding protein (L-FABP) were evaluated before and 2, 4, 8, 24, and 48 hours after cardiac catheterization using commercially available kits. Results. In both groups we found a significant rise in serum NGAL after 2, 4, and 8 hours, and in urinary NGAL and IL-18 after 4, 8, and 24 hours after cardiac catheterization. Serum cystatin C increased significantly 8 hours, reaching peak 24 hours after cardiac catheterization in both groups, and then decreased after 48 hours. L-FABP and KIM-1 increase significantly after 24 and 48 hours after cardiac catheterization. Conclusions. CIN was similarly prevalent in both diabetic and non-diabetic patients undergoing cardiac catheterization. NGAL seems to be a potential early marker for nephrotoxicity and predictor of contrast nephropathy. It is particularly important in the upcoming setting of short-time hospitalizations for cardiac catheterization.     

CURE-UAB: shedding light on the underactive bladder syndrome

Acute kidney injury (AKI) is a very frequent and serious clinical problem, accounting for overall high morbidity and mortality. Up to date, mortality due to AKI is virtually unchanged over the past 50 years. This may partly be explained due to a delay in initiating renal protective and appropriate therapeutic measures since until now there are no reliable early-detecting biomarkers. The gold standard, serum creatinine, displays poor specificity and sensitivity with regard to identification of the incipient phase of AKI, and this is also true for cystatin C. We aimed to review novel biomarkers of AKI in urine and serum which have now progressed to the clinical phase. The main focus refers to their diagnostic and prognostic value. For this purpose, a web-based literature search using PubMed was performed comprising the following terms: renal failure, acute kidney injury and biomarkers. New molecules such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), N-acetyl-β-d-glucosaminidase (NAG), monocyte chemotactic peptide (MCP-1), Il-18, liver-type fatty acid-binding protein (L-FABP) and Netrin-1 are available and represent promising new markers that, however, need to be further evaluated in the clinical setting for suitability. In clinical settings with incipient AKI, not only the development and the implementation of more sensitive, practicable and accurate biomarkers are required for well-timed treatment initiation. Just as important is a substantial improvement of refined and applicable prophylactic therapeutic options in these situations. Before full adoption in clinical practice can be accomplished, adequately powered clinical trials testing a row of biomarkers are strongly warranted.     

Are there any new reliable markers to detect renal injury in obese children?

Aim: The aim of this study was to examine the serum and urine levels of kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), osteopontin (OPN), matrix metalloproteinase-9 (MMP-9), and serum Cystatin-C to determine the renal effect of obesity in obese children.

Methods: Seventy-two obese and 35 non-obese healthy children were included in this study. Blood pressure (BP) was evaluated with office measurement. Creatinine, cystatin C, lipids, fasting glucose, and insulin levels were measured, and homeostasis model assessment -insulin resistance (HOMA-IR) was calculated. The urine albumin/creatinine ratio was calculated. The serum and urine KIM-1, NGAL, OPN, and MMP-9 levels were measured.

Results: Serum cystatin-C, triglyceride, and homeostasis model assessment-insulin resistance (HOMA-IR) index were found to be significantly higher in the obese group (p?=?.0001), and high-density lipoprotein (HDL) cholesterol was found to be significantly lower (p?=?.019) in the obese group. No significant differences were found in serum KIM-1, NGAL, OPN or MMP-9 levels between groups (p?>?.05). No significant differences were found in urine KIM-1 and MMP-9 levels (p?>?.05), Urine NGAL, and OPN levels were found significantly higher in obese groups (p?Conclusions: According to our results, although serum KIM-1, NGAL, OPN, MMP-9, and urine MMP-9, urine KIM-1 do not appear to be ideal markers to evaluate renal injury in the early period of obesity, the serum levels of cystatin C and urine NGAL, urine OPN can be used as a good marker for assessing the renal effect of obesity which can lead end stage renal disease in pediatric population.     

Urinary netrin-1 and KIM-1 as early biomarkers for septic acute kidney injury

Background: Acute kidney injury (AKI) during sepsis is associated with poor outcome. However, diagnosis of AKI with serum creatinine (SCr) level change is neither highly sensitive nor specific. Therefore, identification of novel biomarkers for early diagnosis of AKI is desirable. Aims: To evaluate the capacity of combining urinary netrin-1 and human kidney injury molecule type 1 (KIM-1) in the early diagnosis of septic AKI. Methods: We prospectively recruited 150 septic patients from Jun 2011 to Jun 2013 at Zhejiang Provincial People's Hospital, China. SCr, urinary netrin-1, and KIM-1 levels were recorded at 0, 1, 3, 6, 24, and 48?h of ICU admission and compared between AKI and non-AKI patients. In addition, we investigated the prognostic value of netrin-1 and KIM-1 between non-survivors and survivors in septic AKI patients. Results: SCr levels started to show elevation after 24?h of ICU admission. However, netrin-1 levels increased significantly as early as 1?h, peaked at 3–6?h and remained elevated up to 48?h of ICU admission in septic AKI patients. KIM-1 increased significantly by 6?h, peaked at 24?h and remained significantly elevated until 48?h of ICU admission. Furthermore, we observed significant higher urinary KIM-1 levels at 24?h and 48?h in non-survivors compared to survivors in AKI patients. Conclusions: Our results suggest that both netrin-1 and KIM-1 are clinically useful as early biomarkers in the diagnosis of septic AKI. In addition, persistent elevation of urinary KIM-1 level may be associated with poor prognosis.     

Urinary cystatin C as an early biomarker of acute kidney injury following adult cardiothoracic surgery

There is a need to develop early biomarkers of acute kidney injury following cardiac surgery, where morbidity and mortality are increased by its presence. Plasma cystatin C (CyC) and plasma and urine Neutrophil Gelatinase Associated Lipocalin (NGAL) have been shown to detect kidney injury earlier than changes in plasma creatinine in critically ill patients. In order to determine the utility of urinary CyC levels as a measure of kidney injury, we prospectively collected plasma and urine from 72 adults undergoing elective cardiac surgery for analysis. Acute kidney injury was defined as a 25% or greater increase in plasma creatinine or renal replacement therapy within the first 72 hours following surgery. Plasma CyC and NGAL were not useful predictors of acute kidney injury within the first 6 hours following surgery. In contrast, both urinary CyC and NGAL were elevated in the 34 patients who later developed acute kidney injury, compared to those with no injury. The urinary NGAL at the time of ICU arrival and the urinary CyC level 6 hours after ICU admission were most useful for predicting acute kidney injury. A composite time point consisting of the maximum urinary CyC achieved in the first 6 hours following surgery outperformed all individual time points. Our study suggests that urinary CyC and NGAL are superior to conventional and novel plasma markers in the early diagnosis of acute kidney injury following adult cardiac surgery.     

Urinary biomarkers in the early detection and follow-up of tubular injury in childhood urolithiasis

Background

To investigate relationships among urinary biomarkers [kidney injury molecule-1 (KIM-1), N-acetyl-β-glucosaminidase (NAG)], neutrophil gelatinase-associated lipocalin (NGAL) levels and renal tubular injury in childhood urolithiasis.

Methods

Seventy children [36 girls, mean age: 7.3 ± 5.0 years (0.5–18.2)] with urolithiasis/microlithiasis and 42 controls [18 girls, mean age: 8.5 ± 3.8 years (0.9–16.2)] were included in this multicenter, controlled, prospective cohort study. Patients were evaluated three times in 6-month intervals (0, 6 and 12th months). Anthropometric data, urinary symptoms, family history and diagnostic studies were recorded. Urine samples were analyzed for metabolic risk factors (urinary calcium, uric acid, oxalate, citrate, cystine, magnesium, and creatinine excretion), and the urinary KIM-1, NAG, and NGAL levels were measured.

Results

Stones were mostly located in the upper urinary system (82.9%), and six patients (8.6%) had hydronephrosis. Thirty patients (42.9%) had several metabolic risk factors, and the most common metabolic risk factor was hypocitraturia (22.9%). Urinary KIM-1/Cr, NAG/Cr and NGAL/Cr ratios were not significantly different between patients and controls. Furthermore, no significant changes in their excretion were shown during follow-up. Notably, the urinary KIM-1/Cr, NAG/Cr, and NGAL/Cr levels were significantly higher in children under 2 years of age (p = 0.011, p = 0.006, and 0.015, respectively). NAG/Cr and NGAL/Cr ratios were significantly increased in patients with hydronephrosis (n = 6, p = 0.031 and 0.023, respectively).

Conclusions

The results of this study suggest that none of the aforementioned urinary biomarkers (KIM-1, NAG and NGAL levels) may be useful for the early detection and/or follow-up of renal tubular injury and/or dysfunction in childhood urolithiasis.