Urinary Interleukin-6 Research Articles

Urinary Interleukin 18 for Detection of Acute Kidney Injury: A Meta-analysis

Interleukin 18 (IL-18) has been proposed as a biomarker for the early detection of acute kidney injury (AKI), but a broad range of its predictive accuracy has been reported. Meta-analysis of diagnostic test studies. Various clinical settings of AKI, including after cardiac surgery, after contrast infusion, in the emergency department, or in the intensive care unit. Prospective studies that investigated the diagnostic accuracy of IL-18 level to predict AKI. Increasing or increased urinary IL-18 excretion. The primary outcome was AKI development, mainly based on serum creatinine level (definition varied across studies). The other outcome was in-hospital mortality. We analyzed data from 23 studies and 7 countries involving 4,512 patients. Of these studies, 18 could be included in the meta-analysis. Across all settings, the diagnostic odds ratio (DOR) for urinary IL-18 level to predict AKI was 4.22 (95% CI, 2.90-6.14), with sensitivity and specificity of 0.58 and 0.75, respectively. The area under the receiver operating characteristic curve (AUROC) of urinary IL-18 level to predict AKI was 0.70 (95% CI, 0.66-0.74). Subgroup analysis showed the DOR/AUROC of urinary IL-18 was 5.32 (95% CI, 2.92-9.70)/0.72 (95% CI, 0.68-0.76) in cardiac surgery patients and 3.65 (95% CI, 1.88-7.10)/0.66 (95% CI, 0.62-0.70) in intensive care unit or coronary care unit patients. After stratification for age, IL-18 level had better diagnostic accuracy in children and adolescents versus adults: 8.12 (95% CI, 3.79-17.41)/0.78 (95% CI, 0.75-0.82) versus 3.31 (95% CI, 2.28-4.80)/0.66 (95% CI, 0.62-0.70). There was no significant difference in predictive performance of urinary IL-18 level among various times. Various clinical settings; different definition of AKI and serum creatinine level as the reference standard test for the diagnosis of AKI. Urinary IL-18 is a useful biomarker of AKI with moderate predictive value across all clinical settings.

Multiplex Protein Signature for the Detection of Bladder Cancer in Voided Urine Samples

Accurate urine assays for bladder cancer detection would benefit patients and health care systems. Through extensive genomic and proteomic profiling of urine components we previously identified a panel of 8 biomarkers that can facilitate the detection of bladder cancer in voided urine samples. In this study we confirmed this diagnostic molecular signature in a diverse multicenter cohort. We performed a case-control, phase II study in which we analyzed voided urine from 102 subjects with bladder cancer and 206 with varying urological disorders. The urinary concentration of 8 biomarkers (IL-8, MMP-9 and 10, PAI-1, VEGF, ANG, CA9 and APOE) was assessed by enzyme-linked immunosorbent assay. Diagnostic performance of the panel of tested biomarkers was evaluated using ROCs and descriptive statistical values, eg sensitivity and specificity. Seven of the 8 urine biomarkers were increased in subjects with bladder cancer relative to those without bladder cancer. The 7 biomarkers were assessed in a new model, which had an AUROC of 0.88 (95% CI 0.84-0.93), and 74% sensitivity and 90% specificity. In contrast, the sensitivity of voided urine cytology and the UroVysion® cytogenetic test in this cohort was 39% and 54%, respectively. Study limitations include analysis performed on banked urine samples and the lack of voided urine cytology and cytogenetic test data on controls. The study provides further evidence that the reported panel of diagnostic biomarkers can reliably achieve the noninvasive detection of bladder cancer with higher sensitivity than currently available urine based assays.

Clinical values of urinary IL-6 in asymptomatic renal hematuria and renal hematuria with proteins

Renal hematuria is caused by glomerular disease. Under pathological conditions, the distribution of interleukin-6 (IL-6) in kidney tissue is abnormal and urinary IL-6 levels are increased. Abnormal IL-6 secretion promotes the hyperplasia of mesangial cells and matrix and, thus, affects the permeability of the glomerular filtration membrane. Therefore, the detection of urinary IL-6 levels in patients with renal hematuria is beneficial for disease evaluation. A total of 82 patients with primary renal hematuria were divided into group 1 (UPr/24 h < 150 mg; pure hematuria group), group 2 (150 mg ≤ UPr/24 h ≤ 1,000 mg) and group 3 (UPr/24 h > 1,000 mg). A total of 30 normal individuals were selected as the controls. The urinary IL-6 levels were detected by the enzyme-linked immunosorbent assay (ELISA) method and a renal biopsy was conducted. The urinary IL-6 levels and renal pathological damage scores in groups 1 and 2 were significantly reduced compared with those in group 3, (P<0.001 and 0.01, respectively), with no significant difference between groups 1 and 2 (P>0.05). The correlation coefficient (r) of urinary IL-6 with 24 h urinary protein (UPr/24 h) in groups 1, 2 and 3 was 0.017, 0.045 and 0.747, respectively, and that of urinary IL-6 with renal pathological damage score was 0.627, 0.199 and 0.119, respectively. The UPr/24 h was significantly correlated with IL-6 level (r=0.7320, P<0.000). In group 1, the urinary IL-6 levels were correlated with the degree of renal pathological damage. A positive correlation was observed between urinary IL-6 levels and UPr/24 h.

Increased Plasma Tissue Inhibitors of Metalloproteinase Concentrations as Negative Predictors Associated With Deterioration of Kidney Allograft Function Upon Long-Term Observation

Chronic allograft injury (CAI) is the most frequent cause of progressive kidney allograft impairment and eventual loss, which is due to interstitial fibrosis and tubular atrophy (IF/TA). Mechanisms of CAI are not fully understood. Chemokines, cytokines, metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) play roles in fibrosis development. The aims of this study were to evaluate plasma and urine TIMPs (TIMP-1 and TIMP-2), MMPs (MMP-2 and MMP-9), proinflammatory interleukin-6 (IL-6), chemokine (C-C motif) ligand 2 (CCL2 chemokines previously known as monocyte chemoattractant protein-1 [MCP-1]) among 150 recipients beyond 1 year post–renal transplantations and to explore the usefulness of these potential biomarkers of ongoing allograft injury. Renal transplant recipients compared with healthy volunteers (control group) showed significantly increased plasma and urine IL-6, MMP-9, TIMP-1, and TIMP-2, as well as lower plasma MMP-2 and urine CCL2 concentrations. Compared with recipients showing good function those with impairments displayed higher plasma TIMP-1 (P < .001) and TIMP-2 (P = .003) concentrations. The recipient estimated glomerular filtration rate (eGFR) values negatively correlated with plasma TIMP-1 and TIMP-2 levels (r = −0.43; P < .0001 and rs = −0.42; P < .0001, respectively) and with urine IL-6 excretion (rs = −0.33; P < .0001). Multivariate and receiver operating characteristic (ROC) analyses showed TIMP-1 plasma level assessments to be useful estimates of allograft injury.

Mineralocorticoid Receptor Blockade Reduced Oxidative Stress in Renal Transplant Recipients: A Double-Blind, Randomized Pilot Study

Background: Previous experimental studies from our laboratory have demonstrated that aldosterone plays a central role in renal ischemic processes. This study was designed to evaluate the effect of mineralocorticoid receptor blockade in renal transplant recipients from living donors. Methods: 20 adult kidney transplant recipients from living donors were included in a double-blind, randomized, placebo-controlled clinical pilot study that compared spironolactone and placebo. Placebo or spironolactone (25 mg) was administered 1 day before and 3 days posttransplantation. Renal function and urinary kidney injury molecule-1, interleukin-18, and heat shock protein 72 as well as urinary hydrogen peroxide (H₂O₂) levels were quantified. Results: No significant differences were seen between the groups studied regarding age, gender, indication for kidney transplantation, residual renal function, renal replacement therapy, or warm and cold ischemia periods. In contrast, spironolactone administration significantly reduced the oxidative stress assessed by the urinary H₂O₂ excretion, in spite of no differences in renal function or reduction in tubular injury biomarkers. Conclusions: The findings of this exploratory study strongly suggest that aldosterone promotes oxidative stress and that the administration of spironolactone reduces the production of urinary H₂O₂ as a result of lesser formation of surrogate reactive oxygen species secondary to the ischemia-reperfusion phenomenon.

Performance of Kidney Injury Molecule-1 and Liver Fatty Acid-Binding Protein and Combined Biomarkers of AKI after Cardiac Surgery

AKI is common and novel biomarkers may help provide earlier diagnosis and prognosis of AKI in the postoperative period. This was a prospective, multicenter cohort study involving 1219 adults and 311 children consecutively enrolled at eight academic medical centers. Performance of two urine biomarkers, kidney injury molecule-1 (KIM-1) and liver fatty acid-binding protein (L-FABP), alone or in combination with other injury biomarkers during the perioperative period was evaluated. AKI was defined as doubling of serum creatinine or need for acute dialysis. KIM-1 peaked 2 days after surgery in adults and 1 day after surgery in children, whereas L-FABP peaked within 6 hours after surgery in both age groups. In multivariable analyses, the highest quintile of the first postoperative KIM-1 level was associated with AKI compared with the lowest quintile in adults, whereas the first postoperative L-FABP was not associated with AKI. Both KIM-1 and L-FABP were not significantly associated with AKI in adults or children after adjusting for other kidney injury biomarkers (neutrophil gelatinase-associated lipocalin and IL-18). The highest area under the curves achievable for discrimination for AKI were 0.78 in adults using urine KIM-1 from 6 to 12 hours, urine IL-18 from day 2, and plasma neutrophil gelatinase-associated lipocalin from day 2 and 0.78 in children using urine IL-18 from 0 to 6 hours and urine L-FABP from day 2. Postoperative elevations of KIM-1 associate with AKI and adverse outcmes in adults but were not independent of other AKI biomarkers. A panel of multiple biomarkers provided moderate discrimination for AKI.

Abstract 5136: Bladder cancer diagnostic algorithms in hematuria populations.

Abstract Queens University Belfast, the Belfast Health Trust and Randox Laboratories are working together to create risk and diagnostic classifiers for patients with haematuria. Biomarker profiles may fail to differentiate between all possible causes of hematuria, but it would be a huge advancement if benign and malignant causes were differentiated. Our objective was to determine whether single biomarkers or multivariate algorithms could significantly improve on the predictive power of an algorithm based on demographics for detection of urothelial cancer in patients presenting with hematuria. We collected demographic and clinical information from 157 patients (80 urothelial cancers and 77 with confounding pathologies) who had presented with hematuria and were recruited to a case control study. For each patient we measured 22 urinary biomarkers and serum Carcinoembryonic antigen (CEA) using either ELISAs or the Randox biochip technology, BAT. We analysed the collated data, using Forward Wald binary logistic regression analyses. Algorithms based on demographic variables were designated as Prior Predicted Probability (PPP). We then created algorithms incorporating PPP as a single variable, together with biomarkers.We determined Areas under the Receiver Operating Characteristic (AUROC) for differentially expressed single biomarkers and multivariate algorithms. AUROC for CEA, Bladder Tumour Antigen (BTA) and Nuclear matrix protein (NMP22) = 0.74; 0.74; and 0.79, respectively. Vascular endothelial growth factor, dDimer, Fas, hyaluronidase, interleukin(IL) IL-1α, IL-6 and IL-8 were also differentially expressed (T-test; p &amp;lt; 0.05). PPP included age and smoking years. In combination, PPP, NMP22 and Epidermal Growth Factor (EGF) achieved AUROC = 0.90, significantly improving upon the AUROC for PPP which was 0.76. Although neutrophil-associated gelatinase lipocalin (NGAL) levels were similar in urines from UC and control patients, a multivariate classifier which comprised age, serum CEA and urinary NGAL and interleukin 8 achieved a respectable AUROC = 0.844. Biomarkers significantly improved upon the AUROC statistic based on demographics. Despite non differential urinary levels across UC and controls, NGAL made a significant contribution to a diagnostic classifier exemplifying the unpredictable nature of the complexities involved in collectives of biomarkers. The impact of biomarkers in multivariate algorithms for bladder cancer diagnosis in patients with hematuria. Abogunrin F, O'Kane HF, Ruddock MW, Stevenson M, Reid CN, O'Sullivan JM, Anderson NH, O'Rourke D, Duggan B, Lamont JV, Boyd RE, Hamilton P, Nambirajan T, Williamson KE. Cancer. May 15;118(10) [2012] American Cancer Society Inc Citation Format: Michael Stevenson, Cherith Reid, Brian Duggan, Mark Ruddock, Kate E. Williamson. Bladder cancer diagnostic algorithms in hematuria populations. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5136. doi:10.1158/1538-7445.AM2013-5136

Usefulness of Urinary Immune Biomarkers in the Evaluation of Neonatal Sepsis

Our hypothesis is that specific proinflammatory and anti-inflammatory urinary cytokines are useful in the diagnostic evaluation of risk for sepsis in term neonates. We conducted a pilot, prospective hospital-based longitudinal observational study to test the urine of term neonates with a 13 biomarker panel of cytokines. Infants were divided into 2 groups: The control group (n = 15) consisted of infants admitted to newborn nursery, and the test group (n = 15) consisted of infants admitted to the neonatal intensive care unit for presumed sepsis. Bagged urine samples were collected from 30 term neonates for testing our hypothesis. Urinary interleukin (IL)-8 (P = .004*), inducible protein (IP)-10 (P = .007*), and monocyte chemoattractant protein (MCP)-1 (P = .02) were significantly increased in the test group compared with the control group. Urinary IL-8, IP-10, and MCP-1 are proinflammatory cytokines that are increased in the neonate during an infectious inflammatory process. These may be useful predictors as an adjunct to the current protocols to recognize neonatal sepsis.

ATP-P2X4 signaling mediates NLRP3 inflammasome activation: A novel pathway of diabetic nephropathy

Tubulointerstitial inflammation plays a key role in the development of diabetic nephropathy (DN). Cytokines in the IL-1 family are the key pro-inflammatory cytokines of tubulointerstitial inflammation. Extracellular ATP can cause P2X receptors to activate the NOD-like receptor 3 (NLRP3) inflammasome and cause IL-1β and IL-18 maturation and release. We investigated the role of ATP-P2X4 signaling in NLRP3 inflammasome activation and renal interstitial inflammation characteristic of DN. Ex vivo studies, P2X4 showed increased expression in renal tubule epithelial cells in patients with nephropathy due to type 2 diabetes compared to those in the control group. Linear correlation analysis shows that P2X4 expression was positively related with urine IL-1β and IL-18 levels. Moreover, P2X4 expression was co-localized with NLRP3, IL-1β, and IL-18 expression. In vitro culture experiments showed NLRP3 protein expression, cleavage of caspase-1 and IL-1β, and release of IL-1β, IL-18 and ATP in HK-2 cells significantly increased after high glucose stimulation. However, apyrase, which consumes extracellular ATP, completely blocked the changes caused by high glucose. The P2 receptor antagonist suramin, P2X receptor antagonist TNP-ATP, P2X4 selective antagonist 5-BDBD, and P2X4 gene silencing attenuated NLRP3 expression, cleavage of caspase-1 and IL-1β, and release of IL-1β and IL-18 induced by high glucose. Taken together, these results suggest that ATP-P2X4 signaling mediates high glucose-induced activation of the NLRP3 inflammasome, regulates IL-1 family cytokine secretion, and causes the development of tubulointerstitial inflammation in DN.

Implication of combined urinary biomarkers in early diagnosis of acute kidney injury following percutaneous coronary intervention

Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and interleukin 18 (IL-18) are three of the most promising biomarkers for the early detection of acute kidney injury. In the present study, to determine whether a combination of the three biomarkers enhances their predictive value, representing an ideal indicator for the early detection of Acute Kidney Injury (AKI) we examined 118 adults undergoing elective percutaneous coronary intervention (PCI). We performed a single center, nested case-control study. Urinary KIM-1, NGAL and IL-18 were measured by enzyme-linked immunosorbent assay before and 6 h, 24 h, 48 h postcontrast. Serum creatinine was measured before and 24 h, 48 h postcontrast. 12 patients (10.1%) were identified with AKI. 30 patients were selected as controls, matched with cases at an attempted 2.5 : 1 ratio. Compared to the non-AKI group, urinary NGAL were significantly higher at all the time-points. Urinary KIM-1 and IL-18 levels were significantly higher at 24 h and 48 h postcontrast. In the AKI group, Urinary NGAL peaked at 6 h postcontrast, and then decreased. Both KIM-1 and IL-18 peaked at 24 hours postcontrast, remained markedly elevated up to 48 h. By applying area under the receiver operator characteristic curve, the combination of KIM-1, NGAL and IL-18 had the most powerful diagnostic power (AUC = 0.99, (95%CI: 0.90 - 1.00), p = 0.0001) for diagnosis of AKI at 24 h postcontrast, superior to that for single detection and serum creatinine. KIM-1, NGAL and IL-18 were increased in tandem after PCI. The combination of urinary biomarkers may allow for early detection of AKI following PCI, better than serum creatinine, and the individual biomarkers.

Effects of Herpes Simplex Virus Vector–Mediated Enkephalin Gene Therapy on Bladder Overactivity and Nociception

We previously reported the effects of herpes simplex virus (HSV) vector-mediated enkephalin on bladder overactivity and pain. In this study, we evaluated the effects of vHPPE (E1G6-ENK), a newly engineered replication-deficient HSV vector encoding human preproenkephalin (hPPE). vHPPE or control vector was injected into the bladder wall of female rats 2 weeks prior to the following studies. A reverse-transcription PCR study showed high hPPE transgene levels in L6 dorsal root ganglia innervating the bladder in the vHPPE group. The number of freezing behaviors, which is a nociceptive reaction associated with bladder pain, was also significantly lower in the vHPPE group compared with the control group. The number of L6 spinal cord c-fos-positive cells and the urinary interleukin (IL)-1β and IL-6 levels after resiniferatoxin (RTx) administration into the bladder of the vHPPE group were significantly lower compared with those of the control vector-injected group. In continuous cystometry, the vHPPE group showed a smaller reduction in intercontraction interval after RTx administration into the bladder. This antinociceptive effect was antagonized by naloxone hydrochloride. Thus, the HSV vector vHPPE encoding hPPE demonstrated physiological improvement in visceral pain induced by bladder irritation. Gene therapy may represent a potentially useful treatment modality for bladder hypersensitive disorders such as bladder pain syndrome/interstitial cystitis.

Editorial Comment to Interleukin‐6 levels in female rats with protamine sulfate‐induced chronic cystitis treated with hyaluronic acid

In the present study, Lv et al. investigated the correlation between interleukin (IL)-6 levels and the inflammatory degree, as well as the voiding frequency in protamine sulfate-induced chronic cystitis rats with or without treatment of hyaluronic acid.1 They concluded that tissue levels of IL-6 might be an effective assessment of the therapeutic impact of interstitial cystitis/bladder pain syndrome (IC/PBS). Currently, although there are some candidate biomarkers for IC/PBS; that is, phenylacetylglutamine and nerve growth factor,2, 3 which have not been widely used in a clinical setting and are only experimental. In the current study, the authors suggest that IL-6 might be a reliable marker of IC/PBS. IL-6 is one of the cytokines related to inflammation, and I wonder about the sensitivity and the specificity of IL-6 in IC/PBS. In addition, the urinary levels of IL-6 (urinary IL-6/urinary creatinine) might be a better marker rather than the tissue levels of IL-6 in clinical use. Although the protocol and data in these experiments are clearly shown and interesting, further clinical trials are necessary in order to evaluate the role of IL-6 in IC/PBS in the urine and bladder tissue. None declared.

Urinary biomarkers and renal near-infrared spectroscopy predict intensive care unit outcomes after cardiac surgery in infants younger than 6 months of age

To assess the ability of urinary acute kidney injury biomarkers and renal near-infrared spectroscopy (NIRS) to predict outcomes in infants after surgery for congenital heart disease. Urinary levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin-18 (IL-18), kidney injury molecule-1 (KIM-1), and cystatin C were measured preoperatively and postoperatively in 49 infants younger than 6 months of age. Renal NIRS was monitored for the first 24 hours after surgery. A composite poor outcome was defined as death, the need for renal replacement therapy, prolonged time to first extubation, or prolonged intensive care unit length of stay. Forty-two (86%) patients had acute kidney injury as indicated by at least Acute Kidney Injury Network/Kidney Disease: Improving Global Outcomes (AKIN/KDIGO) stage 1 criteria, and 17 (35%) patients had poor outcomes, including 3 deaths. With the exception of KIM-1, all biomarkers demonstrated significant increases within 24 hours postoperatively among patients with poor outcomes. Low levels of NGAL and IL-18 demonstrated high negative predictive values (91%) within 2 hours postoperatively. Poor outcome infants had greater cumulative time with NIRS saturations less than 50% (60 vs 1.5 minutes; P=.02) in the first 24 hours. Within the first 24 hours after cardiopulmonary bypass, infants at increased risk for poor outcomes demonstrated elevated urinary NGAL, IL-18, and cystatin C and increased time with low NIRS saturations. These findings suggest that urinary biomarkers and renal NIRS may differentiate patients with good versus poor outcomes in the early postoperative period, which could assist clinicians when counseling families and inform the development of future clinical trials.

Evaluation of the diagnostic performance of new markers for acute kidney injury associated with contrast administration

Background: Contrast-induced nephropathy (CIN) is a form of acute kidney injury (AKI) that is caused by exposure to contrast media in diagnostic imaging and interventional procedures such as angiography. At present serum creatinine is the only standard test for it. A few studies have been published analyzing the potential use of neutrophil-gelatinase-associated lipocalin (NGAL) in AKI. Aim: The aim of this study is to search for new markers to identify AKI acute renal failure earlier than serum creatinine. Materials and Methods: We studied 100 consecutive patients with normal serum creatinine undergoing angiographic procedure against Urine NGAL, serum NGAL, serum Cystatin C and urinary interleukin-18 (IL-18) at basal, and 2 h, 4 h, 8 h, 24 h, and 48 h after the angiography. Results: There was a significant rise in serum NGAL levels at 2 h, 4 h, and 8 h after angiography and in urinary NGAL levels at 4 h, 8 h, and 24 h after the procedure. Cystatin C rose significantly at 8 h and 24 h after the procedure, On the other hand, there was mild rise in urinary Il-18 levels at 24 h, but not significant. The presence of CIN associated with AKI was 13%. Conclusion: The present study highlighted the importance of serum NGAL, urine NGAL and Cystatin C in detecting AKI associated with contrast administration earlier than serum creatinine.

Paclitaxel-Fe3O4 nanoparticles inhibit growth of CD138&amp;ndash;&amp;nbsp; CD34&amp;ndash; tumor stem-like cells in multiple myeloma-bearing mice

BackgroundThere is growing evidence that CD138− CD34− cells may actually be tumor stem cells responsible for initiation and relapse of multiple myeloma. However, effective drugs targeted at CD138− CD34− tumor stem cells are yet to be developed. The purpose of this study was to investigate the inhibitory effect of paclitaxel-loaded Fe3O4 nanoparticles (PTX-NPs) on CD138− CD34− tumor stem cells in multiple myeloma-bearing mice.MethodsCD138− CD34− cells were isolated from a human U266 multiple myeloma cell line using an immune magnetic bead sorting method and then subcutaneously injected into mice with nonobese diabetic/severe combined immunodeficiency to develop a multiple myeloma-bearing mouse model. The mice were treated with Fe3O4 nanoparticles 2 mg/kg, paclitaxel 4.8 mg/kg, and PTX-NPs 0.64 mg/kg for 2 weeks. Tumor growth, pathological changes, serum and urinary interleukin-6 levels, and molecular expression of caspase-3, caspase-8, and caspase-9 were evaluated.ResultsCD138− CD34− cells were found to have tumor stem cell characteristics. All the mice developed tumors in 40 days after injection of 1 × 106 CD138− CD34− tumor stem cells. Tumor growth in mice treated with PTX-NPs was significantly inhibited compared with the controls (P < 0.005), and the groups that received nanoparticles alone (P < 0.005) or paclitaxel alone (P < 0.05). In addition, the PTX-NPs markedly inhibited interleukin-6 secretion, increased caspase-8, caspase-9, and caspase-3 expression, and induced apoptosis of tumor cells in the treated mice.ConclusionPTX-NPs proved to be a potent anticancer treatment strategy that may contribute to targeted therapy for multiple myeloma tumor stem cells in future clinical trials.

Acute renal failure in cirrhotic patients with severe sepsis: Value of urinary interleukin‐18

Acute renal failure (ARF) is a common complication of liver cirrhosis and severe sepsis. Differentiating functional renal failure from acute tubular necrosis (ATN) has been difficult in this clinical setting. It has been shown that urinary interleukin 18 (IL-18) can serve as a sensitive marker for ARF and ATN. This study was aimed to investigate the diagnostic and prognostic values of urinary IL-18 in ARF associated with liver cirrhosis and severe sepsis. We prospectively evaluated the relationship between urinary IL-18 and clinical outcomes in 168 consecutive cirrhotic patients with severe sepsis. One hundred and eight patients (64.3%) developed ARF at admission to the intensive care unit. ARF was associated with higher urinary IL-18 and impaired effective arterial volume. Renal failure was functional in 64 (59.2%), due to acute tubular necrosis (ATN) in 30 (27.7%), and mixed type in 14 (12.9%). Patients with ATN had significantly higher levels of urinary IL-18, rates of vasopressor dependency, and hospital mortality than those with functional renal failure. By using the areas under receiver operating characteristic (AUROC) curve, urinary IL-18 demonstrated an excellent discriminative power (AUROC 0.882) for diagnosing tubular injury in those with ARF. Meanwhile, hospital survivors had significantly lower urinary and serum IL-18 levels, compared to non-survivors. In multivariate analysis, urinary IL-18, international normalized ratio, and mean arterial pressure were independent factors to predict hospital mortality. Urinary IL-18 can serve as a diagnostic and prognostic marker in cirrhotic patients with severe sepsis.

Characteristics of changes in urinary NGAL, KIM-1 and IL-18 in Phytolaccae Radix-induced renal injury in rats and significance of combined detection

To explore the characteristics of changes in neutrophil gelatinase-associated lipocalcin (NGAL), kidney injury molecule-1 (KIM-1) and interleukin-18 (IL-18) in Phytolaccae Radix-induced kidney injury in rats and the significance of the combined detection. Wistar rats were divided into three groups: high and low dose (crude drug 40, 20 g x kg(-1) x d(-1)) Phytolaccae Radix decoction groups and the control group, and orally administrated with distilled water or equal volume of Phytolaccae Radix decoction for 35 consecutive days. Their blood and urine samples were collected on day 7, 14, 21, 28, 35,42. The anatomical analysis was conducted for each group. The contents of serum total protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (CR) and urinary TP and ALB were detected-by means of biochemical analyzer. The concentrations of urinary NGAL, KIM-1 and IL-18 were measured by enzyme-linked immunosorbent assay (ELISA). The morphological changes of renal pathology were observed by light or electron microscopy. The curve areas of various serum or urine indexes and the combined detection were compared by receiver operating characteristic curve (ROC curve). Rats were given Phytolaccae Radix decoction at the doses of 40, 20 g crude drug/kg daily for 35 consecutive days to induce kidney injury characterized by the degeneration of renal tubular epithelial cell and protein cast. The injury was partially reversible during the recovery period. Compared with the control group, the content of serum BUN, CR and urinary TP in each dose group mostly showed a downward trend. On day 21, the content of urinary ALB obviously increased till the end of administration. The contents of urinary NGAL, KIM-1 and IL-18 began increasing on day 7. Since day 14, high and low dose groups showed significant difference (P<0.01). The high dose group even showed notable changes during the recovery period. According to ROC analysis, the curve areas of NGAL, KIM-1 and IL-18 were 0.846, 0.837 and 0.863 (P <0.01), respectively, much higher than that of BUN and CR. The area of the combined detection was up to 0.947. Urinary NGAL, IL-18 and KIM-1 could forecast and indicate the occurrence and development of renal injury to some degree, and show higher sensitivity and site specificity. The combined detection could further improve the test efficiency.

Results of a Phase 1 Dose Escalation Study of Intravesical TMX-101 in Patients with Nonmuscle Invasive Bladder Cancer

Imiquimod, a toll like receptor 7 (TLR-7) agonist, is effective as a topical treatment for skin malignancies. TMX-101 is a liquid formulation of imiquimod. In this study we establish a safety profile of TMX-101 in patients with nonmuscle invasive bladder cancer. We conducted a multicenter phase 1 dose escalation study in patients with nonmuscle invasive bladder cancer. Patients were included in 1 of 4 dose groups (0.05%, 0.1%, 0.2% or 0.4%) and treated with 6 weekly instillations of TMX-101, starting 2 weeks after transurethral resection of bladder tumor. Patients were evaluated weekly, and pharmacokinetic and pharmacodynamic parameters were measured. A total of 16 patients were included in the study with 4 per dose group. Two patients dropped out after instillation 2 in dose groups 1 and 2. Overall, 88 instillations were administered without serious adverse events. There were 118 adverse events, of which 84 were related to the study drug. All adverse events were mild or moderate and number or severity was not correlated with dose group. Of the related adverse events 70% were confined to the genitourinary tract and resolved without intervention. There was a dose dependent systemic uptake with low plasma levels up to dose group 3 (0.2%, 100 mg). Maximum plasma concentration in dose group 4 (0.4%, 200 mg) was 71.7 ng/ml. This is below plasma concentrations of 123 and 128 ng/ml without significant side effects measured in healthy volunteers after subcutaneous (30 mg) or oral intake (100 mg) of imiquimod, respectively. Intravesical treatment with TMX-101 is safe. The side effects are common but mild and mostly limited to the genitourinary tract. There is a low systemic uptake.

Combination therapy with an angiotensin-converting-enzyme inhibitor and an angiotensin II receptor antagonist ameliorates microinflammation and oxidative stress in patients with diabetic nephropathy.

Recent studies have pointed to the effectiveness of combination therapy with an angiotensin-converting-enzyme inhibitor (ACEI) and an angiotensin receptor blocker (ARB) for diabetic nephropathy. However, some controversy over this combination treatment remains and the mechanisms underlying its renoprotective effects have not been fully clarified. Therefore, we compared the renoprotective effects of imidapril (ACEI) and losartan (ARB) combination therapy with losartan monotherapy in patients with diabetic nephropathy. We also compared the anti-inflammatory and anti-oxidative stress effects of these two treatments. A total of 32 Japanese patients with type2 diabetes and nephropathy were enrolled. Patients were randomized to either 100mg/day losartan (n=16) or 50mg/day losartan plus 5mg/day imidapril (n=16). We evaluated clinical parameters, serum concentrations of high-sensitivity C-reactive protein (hs-CRP), soluble intercellular adhesion molecule-1 (sICAM-1), interleukin-18 (IL-18) and monocyte chemotactic protein-1 (MCP-1), and the urinary concentrations of IL-18, MCP-1 and 8-hydroxy-2'-deoxyguanosine (8-OHdG) at 24 and 48weeks after starting treatment. Blood pressure was not significantly different between the two groups. The serum levels of hs-CRP, sICAM-1 and IL-18, as well as urinary excretion of albumin, IL-18 and 8-OHdG decreased significantly in the combination therapy group at 48weeks. The percent decreases in serum IL-18 concentrations and urinary IL-18 and 8-OHdG were significantly greater in the combination therapy group than in the monotherapy group. Combination therapy with an ACEI and an ARB could be beneficial for treating diabetic nephropathy through its anti-inflammatory and anti-oxidative stress effects.

Neutrophil gelatinase-associated lipocalin is a sensitive biomarker for the early diagnosis of acute rejection after living-donor kidney transplantation

Early diagnosis of kidney allograft dysfunction is crucial for the management and long-term survival of transplanted kidneys. We investigated whether neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), and liver-type fatty acid-binding protein (L-FABP) are capable of being used as novel biomarkers of acute kidney allograft dysfunction. We measured serum and urine NGAL, urine IL-18, and urine L-FABP levels on the first 3 days after transplantation. To assess the diagnostic sensitivity of these biomarkers, a receiver-operating characteristic curve (ROC) was plotted, and the area under the curve (AUC) was calculated to quantify the accuracy of the parameter. Sections from paraffin-embedded biopsy specimens were examined by immunohistochemistry for NGAL expression. Twelve cases were clinically diagnosed as acute rejection (AR) by renal biopsy. Urine NGAL was the most sensitive of these markers for detection of acute kidney allograft dysfunction. The cutoff value of urine NGAL was 66.0 ng/ml, with an AUC of 0.79 (95 % CI 0.68-0.88). Sensitivity of serum NGAL was about the same as urine NGAL with an AUC of 0.75 (0.64-0.85). IL-18 and L-FABP were 0.584 (95 % CI 0.433-0.725) and 0.612 (95 % CI 0.460-0.749), respectively. NGAL was more useful than other biomarkers to detect AR of kidney allograft dysfunction. NGAL staining intensity was significantly increased in the proximal tubules of the transplants with AR than in transplants that were not acutely rejected. Urine NGAL level was found to be the most sensitive biomarker of acute kidney allograft dysfunction after living-donor kidney transplantation.