Perioperative Acute Renal Injury: Revisiting Pathophysiology.

BACKGROUND: Acute renal dysfunction and subsequent acute renal failure after cardiac surgery are associated with high mortality and morbidity. Early therapeutic or preventive intervention is hampered by the lack of an early biomarker for acute renal injury. Recent studies showed that urinary neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2) is upregulated early (within 1 to 3 h) after murine renal injury and in pediatric acute renal dysfunction after cardiac surgery. The authors hypothesized that postoperative urinary NGAL concentrations are increased in adult patients developing acute renal dysfunction after cardiac surgery compared with patients without acute renal dysfunction. METHODS: After institutional review board approval, 81 cardiac surgical patients were prospectively studied. Urine samples were collected immediately before incision and at various time intervals after surgery for NGAL analysis by quantitative immunoblotting. Acute renal dysfunction was defined as peak postoperative serum creatinine increase by 50% or greater compared with preoperative serum creatinine. RESULTS: Sixteen of 81 patients (20%) developed postoperative acute renal dysfunction, and the mean urinary NGAL concentrations in patients who developed acute renal dysfunction were significantly higher early after surgery (after 1 h, mean ± SD, 4,195 ± 6,520 vs. 1,068 ± 2,129 ng/ml; P < 0.01) compared with patients who did not develop acute renal dysfunction. Mean urinary NGAL concentrations continued to increase and remained significantly higher at 3 and 18 h after cardiac surgery in patients with acute renal dysfunction. In contrast, urinary NGAL in patients without acute renal dysfunction decreased rapidly after cardiac surgery. CONCLUSIONS: Patients developing postoperative acute renal dysfunction had significantly higher urinary NGAL concentrations early after cardiac surgery. Urinary NGAL may therefore be a useful early biomarker of acute renal dysfunction after cardiac surgery. These findings may facilitate the early detection of acute renal injury and potentially prevent progression to acute renal failure.

Novel Finding of Urinary Erythropoietin as an Early Biomarker of Cisplatin-Induced Nephrotoxicity.

Cisplatin is a chemotherapeutic drug used to treat a great variety of solid tumors. Its dose is commonly limited by its nephrotoxicity, manifested as acute kidney injury (AKI). Erythropoietin (Epo) is a glycoprotein hormone that regulates the production of red blood cells. This study was performed to evaluate the presence of endogenous Epo in male Wistar rat urine and to analyse changes in urinary Epo levels in response to cisplatin- induced AKI. Dose-dependent studies and time-dependent experiments were performed to evaluate changes in urea nitrogen and creatinine in plasma as well as Epo, neutrophil gelatinase-associated lipocalin (NGAL), alkaline phosphatase (AP) activity, creatinine and total proteins in urine at 2 days post-dosing. Rats received 2, 5 or 10 mg/kg b.w., i.p. of cisplatin. At 5 mg/kg b.w., i.p. cisplatin, significant increases in urinary Epo were detected. Significant increases in urea nitrogen and creatinine in plasma, NGAL, AP, proteins, and Epo were observed in urine from rats that received 10 mg/kg b.w., i.p. of cisplatin. In the time-dependent experiments, rats were injected with a dose of 5 mg/kg b.w., i.p. of cisplatin, and sampling occurred 2, 4, and 14 days post-dosing. In these animals, there were significant increases in urea nitrogen and creatinine in plasma and total proteins, AP activity, Epo, and NGAL in urine on day 4. Urinary Epo was also detected on day 2. Taken together, these findings provide weight of evidence for urinary Epo as a promising early biomarker of cisplatin-induced AKI in male rats.

Urinary Kringle Domain-Containing Protein HGFL: A Validated Biomarker of Early Sickle Cell Anemia-Associated Kidney Disease.

INTRODUCTION: Chronic kidney disease (CKD) is a prevalent complication of sickle cell anemia (SCA). Hyperfiltration that delayed detection of CKD is common in SCA patients. Identification of novel urinary biomarkers correlating with glomerular filtration rates may help to detect and predict progression of renal disease. METHODS: Reanalysis of mass spectra of urinary samples obtained from University of Illinois at Chicago identified kringle domain-containing protein HGFL. RESULTS: HGFL levels correlated with hyperfiltration, were significantly reduced at CKD stage 1 compared to stage 0, negatively correlated with progression of CKD and were suitable for differentiation of stage 1. Better prediction of CKD progression to stage 2 was observed for HGFL-based risk prediction compared to the estimated glomerular filtration rate (eGFR)-based prediction. Results from a Howard University patient cohort supported the utility of HGFL-based test for the differentiation of stage 1 of CKD. CONCLUSION: Urinary HGFL may contribute additional information beyond eGFR and improve diagnosis of early-stage CKD in SCA patients.

Mechanical stimulations can inhibit local and remote tumor progression by downregulating WISP1.

Mechanical stimulations can prevent bone loss, but their effects on the tumor-invaded bone or solid tumors are elusive. Here, we evaluated the effect of knee loading, dynamic loads applied to the knee, on metastasized bone and mammary tumors. In a mouse model, tumor cells were inoculated to the mammary fat pad or the proximal tibia. Daily knee loading was then applied and metabolic changes were monitored mainly through urine. Urine samples were also collected from human subjects before and after step aerobics. The result showed that knee loading inhibited tumor progression in the loaded tibia. Notably, it also reduced remotely the growth of mammary tumors. In the urine, an altered level of cholesterol was observed with an increase in calcitriol, which is synthesized from a cholesterol derivative. In urinary proteins, knee loading in mice and step aerobics in humans markedly reduced WNT1-inducible signaling pathway protein 1, WISP1, which leads to poor survival among patients with breast cancer. In the ex vivo breast cancer tissue assay, WISP1 promoted the growth of cancer fragments and upregulated tumor-promoting genes, such as Runx2, MMP9, and Snail. Collectively, the present preclinical and human study demonstrated that mechanical stimulations, such as knee loading and step aerobics, altered urinary metabolism and downregulated WISP1. The study supports the benefit of mechanical stimulations for locally and remotely suppressing tumor progression. It also indicated the role of WISP1 downregulation as a potential mechanism of loading-driven tumor suppression.

Increased Circulating and Urinary Levels of Soluble TAM Receptors in Diabetic Nephropathy.

TAM receptors (Tyro3, Axl, and Mer) have been implicated in innate immunity. Circulating TAM receptor soluble forms (sTyro3, sAxl, sMer) are related to autoimmune disorders. We investigated TAM and their ligand protein S in patients with diabetes. Urinary and plasma levels of protein S, sTyro3, sAxl, and sMer were determined in 126 patients with diabetes assigned to a normoalbuminuric or macroalbuminuric (urinary albumin excretion <30 mg/24 hours and >300 mg/24 hours, respectively) study group and 18 healthy volunteers. TAM and protein S immunostaining was performed on kidney biopsy specimens from patients with diabetic nephropathy (n = 9) and controls (n = 6). TAM expression and shedding by tubular epithelial cells were investigated by PCR and enzyme-linked immunosorbent assay in an in vitro diabetes model. Patients with macroalbuminuria diabetes had higher circulating levels of sMer and more urinary sTyro3 and sMer than normoalbuminuric diabetics. Increased clearance of sTyro3 and sMer was associated with loss of tubular Tyro3 and Mer expression in diabetic nephropathy tissue and glomerular depositions of protein S. During in vitro diabetes, human kidney cells had down-regulation of Tyro3 and Mer mRNA and increased shedding of sTyro3 and sMer. Renal injury in diabetes is associated with elevated systemic and urine levels of sMer and sTyro3. This is the first study reporting excretion of sTAM receptors in urine, identifying the kidney as a source of sTAM.

Early urinary biomarkers of renal tubular damage by a high-salt intake independent of blood pressure in normotensive rats.

Dietary sodium intake has been associated with progression to chronic kidney disease (CKD) as well as hypertension. A high-salt intake causes renal damage independent of hypertension. Because traditional renal biomarkers are insensitive, it is difficult to detect renal injury induced by a high-salt intake, especially in normotensive patients. Here, we investigated whether newly developed renal biomarkers could be detected earlier than traditional biomarkers under a high-salt intake, in normotensive rats. Male Wistar Kyoto rats (WKY) received a regular (0.8% NaCl) or salt-loaded (2, 4, and 8% NaCl) diet from 9 to 17 weeks of age. A urine sample was obtained once a week and urinary vanin-1, neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (Kim-1) were measured. At 17 weeks of age, 8% salt-loaded WKY showed histopathological renal tubular damage and elevated Rac1 activity in renal tissues. Although there was no significant increase in serum creatinine, urinary albumin, N-acetyl-ß-D-glucosaminidase (NAG), or Kim-1 during the study period among the groups, urinary vanin-1 and NGAL significantly increased in 8% salt-loaded WKY from 10 to 17 weeks of age. These results suggest that urinary vanin-1 and NGAL, which might be induced by salt per se, are potentially earlier biomarkers for renal tubular damage in normotensive rats under a high-salt intake.

Therapeutic Effect of Chrysin on Adenine-Induced Chronic Kidney Disease in Rats.

BACKGROUND/AIMS: To study the therapeutic effect of chrysin, a flavonoid with strong antioxidant and anti-inflammatory activities, on adenine-induced chronic kidney diseases (CKD) in rats. METHODS: Chrysin, in three graded oral doses (10, 50 and 250 mg/kg), was given for 10 consecutive days to rats after the induction of CKD by feeding them adenine (0.25%(w/w) for 35 days). Several plasma and urine biomarkers and tissues morphology were used the investigate chrysin effect on kidney structure and function. RESULTS: Adenine lowered creatinine clearance and elevated the concentrations of urea, creatinine, plasma neutrophil gelatinase-associated lipocalin and urinary N-Acetyl-beta-D-glucosaminidase activity, and increased the concentrations of the uremic toxin indoxyl sulfate, in addition to some inflammatory cytokines. Renal histopathological markers of inflammation and fibrosis were significantly increased. Renal catalase and superoxide dismutase activities, total antioxidant capacity and reduced glutathione were all adversely affected. Most of these adenine - induced actions were moderately mitigated by chrysin, especially at the highest dose. Compared to control, chrysin did not cause any overt adverse effects on the treated rats. CONCLUSION: Different doses of chrysin produce variable therapeutic salutary effects in rats with CKD, and that, pending further studies, its usability as a possible therapeutic agent in human CKD should be considered.

Cardiotrophin-1 therapy prevents gentamicin-induced nephrotoxicity in rats.

Aminoglycosides are very effective antibiotics for the treatment of severe infections, but they rank among the most frequent causes of drug-induced nephrotoxicity. Thus, prevention of aminoglycoside nephrotoxicity is an unmet therapeutic objective. Cardiotrophin-1 (CT-1), a member of the IL-6 family of cytokines, has been reported to protect the kidney against toxic and ischemic acute kidney injury (AKI). We have assessed the effect of rat CT-1 in the severity of gentamicin (G)-induced AKI. Groups of male Wistar rats received the following for 6 consecutive days: i) isotonic saline solution (group CONT), ii) G, 150mg/kg/day, i.p. (group G), iii) CT-1, 100µg/kg/day i.v. (group CT-1), or iv) G and CT-1 at the doses described above. The G group showed a manifest AKI characterized by low creatinine clearance, high plasma creatinine and urea levels, increased urinary excretion of proteins, glucose and AKI markers such as N-acetyl-glucosaminidase, neutrophil gelatinase-associated lipocalin, kidney-injury molecule-1 and T-gelsolin, increased kidney levels of CD-68, iNOS, IL-1ß and TNF-α, and markedly higher histological renal damage and leukocyte infiltration than the CONT and CT-1 groups. Administration of CT-1 together with G reduced almost all of the above-described manifestations of G-induced AKI. The results of this study have potential clinical application, as CT-1 is near to being used as a drug for organ protection.

Atrial natriuretic peptide attenuation of renal ischemia-reperfusion injury after major surgery.

BACKGROUND: Ischemia-reperfusion (I/R) injury is one of the most important pathologic processes causing acute kidney injury. Human atrial natriuretic peptide (hANP) has various effects, including renal protection. The purpose of the present work was to study the effects of intrarenal angiotensin II (Ang II) and investigate the potential of hANP to prevent kidney injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into three groups as follows: (1) sham; (2) I/R (30 min of bilateral renal ischemia followed by 6 h reperfusion); and (3) I/R + hANP (I/R injury + continuous intravenous infusion of hANP at 0.025 µg/kg/min). After 6 h of reperfusion, both renal and plasma Ang II concentrations were measured. Urinary angiotensinogen and neutrophil gelatinase-associated lipocalin were measured before ischemia and 2, 4, and 6 h after reperfusion. To evaluate the renal-protective effects of hANP, serum creatinine was determined 6 and 24 h after reperfusion. In addition, mitochondrial oxygen consumption in kidney cortex was measured in the presence of Ang II and hANP. RESULTS: Renal Ang II concentrations were 24.5 ± 3.9 and 14.2 ± 3.4 pg/mg renal weight in the I/R and I/R + hANP groups, respectively. Urinary angiotensinogen and neutrophil gelatinase-associated lipocalin excretions were elevated after I/R injury. Treatment with hANP significantly attenuated this effect after 4 and 6 h. Oxygen consumption in renal mitochondria increased with the addition of Ang II, which was also attenuated by hANP. CONCLUSIONS: Production of intrarenal Ang II was attenuated by hANP, indicating a potential to diminish renal I/R injury.

A comparison of three commercial platforms for urinary NGAL in critically ill adults.

BACKGROUND: Early biomarkers for acute kidney injury (AKI) diagnosis are needed since an increase in serum creatinine levels is a late marker. Neutrophil gelatinase-associated lipocalin (NGAL) is one of the most promising AKI biomarkers. Prior to routine clinical use, it is necessary to evaluate and validate a high-throughput commercially available method for NGAL detection. The aim of this study was to do an independent validation and comparison of the analytical performance of three different commercially available urine NGAL (uNGAL) assays. METHODS: Urine samples (n=110) were obtained from various patient groups with and without AKI. All urine samples were processed using Architect NGAL assay, Siemens Advia® 2400 NGAL test, and Siemens Dimension Vista® NGAL Test™, based on the three different platforms. RESULTS: Overall, there was good agreement among the three assays: Spearman's rank correlation coefficient between Architect and Vista was 0.989 (95% confidence interval [CI], 0.983-0.993), between Architect and Advia, 0.962 (95% CI, 0.937-0.977), between Vista and Advia 2400, 0.975 (95% CI, 0.961-0.984). We observed a negative bias of Architect compared with the other assays: comparing Architect to Vista, the mean bias was -55.7 ng/mL (95% CI, -74.3 to -37.0 ng/mL); comparing Architect to Advia 2400, the mean bias was -40.9 ng/mL (95% CI, -56.4 to -25.4 ng/nL). The bias is proportional to the concentration of uNGAL and is more pronounced at higher levels, while irrelevant near the tested cutoff levels of 100 and 190 ng/mL. Comparing Vista and Advia 2400, the mean bias was 10.1 ng/mL (95% CI, 1.5-18.8 ng/mL). Intra-assay imprecision was generally acceptable across all assays; coefficient of variation ranged from 0.8% to 5.3%. CONCLUSIONS: All three methods for uNGAL showed acceptable performance for the tested parameters and are comparable with each other at clinically relevant cutoffs. However, Architect yields lower results than the other two methods, with a bias more pronounced at higher uNGAL concentrations, suggesting additional standardization efforts will likely be necessary to better harmonize the uNGAL methods at various clinically relevant cutoffs.

Differentiation of acute pyelonephritis from other febrile states in children using urinary neutrophil gelatinase-associated lipocalin (uNGAL).

BACKGROUND: Acute pyelonephritis is a severe disease which is sometimes difficult to recognize based on clinical symptoms and routinely available diagnostic tests, especially in young children. The aim of this study was to assess the diagnostic value of urinary neutrophil gelatinase-associated lipocalin (uNGAL) as a biomarker of acute pyelonephritis. METHODS: In this case-control study we analyzed 134 children (median age 2.5 years) who were admitted to the Pediatric Clinic of University Hospital Centre Osijek, Croatia. Eighty of them had acute pyelonephritis, while 54 children had febrile state of different etiology including cystitis and they represented the control group. uNGAL, white blood cells, C-reactive protein, urinanalysis, urine culture, kidney ultrasound and a dimercaptosuccinic acid scintigraphic scan were done for each child. uNGAL was measured using chemiluminiscent microparticle immunoassay on ARHITECT i1000SR (Abbott Diagnostics, IL, USA). RESULTS: uNGAL values were significantly higher in children with acute pyelonephritis compared to the control groups (113.6 ng/mL vs. 10.2 ng/mL, p<0.001). A receiver operating characteristic curve comparison was done for tested parameters and encouraging results were obtained for uNGAL (AUC=0.952). A cut-off value of 29.4 ng/mL had 92.5% sensitivity and 90.7% specificity. We showed that uNGAL can also serve in differentiating acute pyelonephritis from cystitis (cut-off 38.5 ng/mL), and for differentiation of cystitis from febrile states with etiology other than urinary tract infection (UTI) (cut-off 20.4 ng/mL). CONCLUSIONS: uNGAL can be a useful diagnostic biomarker in acute pyelonephritis in children, but also in differentiating cystitis from febrile states other than UTI.

Latent AKI is still AKI: the quantification of the burden of renal dysfunction.

The association between pediatric cardiac surgery, acute kidney injury (AKI), and clinical outcomes has been studied several times in the recent literature. In this issue of Critical Care an interesting and original study analyzed the path from causal AKI entities to clinical AKI consequences through the application of structural equation modeling. The authors described the complex connections linking duration of cardiopulmonary bypass, cross clamp-time, and descriptors of low cardiac output syndrome to AKI modeled as a complex variable composed of post-operative serum creatinine increase of 50 % over baseline, urine output <0.5 ml/kg/h, and urine creatinine-normalized neutrophil gelatinase lipocalin within 12 h of surgery. Similarly, the causal relationships between AKI and hard outcomes in the analyzed population were verified and quantified. The authors, for the first time, produce a repeatable coefficient (0.741) that may become a useful quality benchmark and could be applied to test future interventions aiming to reduce the burden of AKI on children's clinical course.

Role of new biomarkers for predicting renal scarring in vesicoureteral reflux: NGAL, KIM-1, and L-FABP.

BACKGROUND: Reflux nephropathy is the most serious complication of vesicoureteral reflux (VUR). The aim of this study was to assess the role of urinary levels of neutrophil-gelatinase-associated lipocalin (NGAL),kidney injury molecule-1 (KIM-1), and liver-type fatty-acid-binding protein (L-FABP) in the early diagnosis of reflux nephropathy in patients with VUR. METHODS: This study assessed 123 patients with primary VUR and 30 healthy children as a control group. The children were divided into five groups: Group A, patients with VUR and renal parenchymal scarring (RPS); Group B, patients with VUR and without RPS; Group C, patients with RPS and resolved VUR; Group D, patients with resolved VUR and without RPS; Group E, healthy reference group. RESULTS: Median urinary NGAL (uNGAL)/Creatinine (Cr) was significantly higher in patients with than those without RPS and the control group (p = 0.0001). Median uKIM-1/Cr was similar in all groups (p = 0.417). Median uL-FABP/Cr was significantly higher in patients with RPS than in the reference group (p < 0.05). CONCLUSIONS: Urinary NGAL levels may be used as a noninvasive diagnostic marker for predicting renal scarring in reflux nephropathy.

Plasma IL-6 and IL-10 Concentrations Predict AKI and Long-Term Mortality in Adults after Cardiac Surgery.

Inflammation has an integral role in the pathophysiology of AKI. We investigated the associations of two biomarkers of inflammation, plasma IL-6 and IL-10, with AKI and mortality in adults undergoing cardiac surgery. Patients were enrolled at six academic centers (n = 960). AKI was defined as a ≥ 50% or ≥ 0.3-mg/dl increase in serum creatinine from baseline. Pre- and postoperative IL-6 and IL-10 concentrations were categorized into tertiles and evaluated for associations with outcomes of in-hospital AKI or postdischarge all-cause mortality at a median of 3 years after surgery. Preoperative concentrations of IL-6 and IL-10 were not significantly associated with AKI or mortality. Elevated first postoperative IL-6 concentration was significantly associated with higher risk of AKI, and the risk increased in a dose-dependent manner (second tertile adjusted odds ratio [OR], 1.61 [95% confidence interval (95% CI), 1.10 to 2.36]; third tertile adjusted OR, 2.13 [95% CI, 1.45 to 3.13]). First postoperative IL-6 concentration was not associated with risk of mortality; however, the second tertile of peak IL-6 concentration was significantly associated with lower risk of mortality (adjusted hazard ratio, 0.75 [95% CI, 0.57 to 0.99]). Elevated first postoperative IL-10 concentration was significantly associated with higher risk of AKI (adjusted OR, 1.57 [95% CI, 1.04 to 2.38]) and lower risk of mortality (adjusted HR, 0.72 [95% CI, 0.56 to 0.93]). There was a significant interaction between the concentration of neutrophil gelatinase-associated lipocalin, an established AKI biomarker, and the association of IL-10 concentration with mortality (P = 0.01). These findings suggest plasma IL-6 and IL-10 may serve as biomarkers for perioperative outcomes.

Furosemide Stress Test and Biomarkers for the Prediction of AKI Severity.

Clinicians have access to limited tools that predict which patients with early AKI will progress to more severe stages. In early AKI, urine output after a furosemide stress test (FST), which involves intravenous administration of furosemide (1.0 or 1.5 mg/kg), can predict the development of stage 3 AKI. We measured several AKI biomarkers in our previously published cohort of 77 patients with early AKI who received an FST and evaluated the ability of FST urine output and biomarkers to predict the development of stage 3 AKI (n=25 [32.5%]), receipt of RRT (n=11 [14.2%]), or inpatient mortality (n=16 [20.7%]). With an area under the curve (AUC)±SEM of 0.87±0.09 (P<0.0001), 2-hour urine output after FST was significantly better than each urinary biomarker tested in predicting progression to stage 3 (P<0.05). FST urine output was the only biomarker to significantly predict RRT (0.86±0.08; P=0.001). Regardless of the end point, combining FST urine output with individual biomarkers using logistic regression did not significantly improve risk stratification (ΔAUC, P>0.10 for all). When FST urine output was assessed in patients with increased biomarker levels, the AUC for progression to stage 3 improved to 0.90±0.06 and the AUC for receipt of RRT improved to 0.91±0.08. Overall, in the setting of early AKI, FST urine output outperformed biochemical biomarkers for prediction of progressive AKI, need for RRT, and inpatient mortality. Using a FST in patients with increased biomarker levels improves risk stratification, although further research is needed.

Tubular Injury Biomarkers to Detect Gentamicin-Induced Acute Kidney Injury in the Neonatal Intensive Care Unit.

OBJECTIVE: We evaluated whether urinary excretion of tubular injury markers could be useful for early detection of gentamicin (GM)-induced renal damage in neonates. STUDY DESIGN: We conducted a prospective, observational trial in neonates admitted to the neonatal intensive care unit (26 GM treated, 20 control). Kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-ß-D-glucosaminidase (NAG), and π- and α-glutathione-S-transferase (GSTP1-1 and GSTA1-1) were measured every 2 hours during admission and compared with serum creatinine (sCr) and urine output. RESULTS: Nine neonates developed AKI during the course of the study. The peak in excretion of urinary biomarkers preceded the peak in sCr (p < 0.0001). GM administration resulted in a more pronounced increase of sCr compared with control (13 [12-28] vs. 10 µmol/L [8.5-17]; p < 0.05). The urinary excretion of NAG (178 [104-698] vs. 32 ng/mol Cr [9-82]; p < 0.001) and NGAL (569 [168-1,681] vs. 222 ng/mol Cr [90-497]; p < 0.05) was higher in the GM group compared with control and preceded the peak of sCr and urine output decrease. CONCLUSION: GM administration to neonates is associated with renal damage reflected by a more pronounced increase in sCr preceded by urinary excretion of biomarkers. Urinary biomarkers may be useful for earlier identification of renal injury in neonates.

[KIM-1 and NGAL as potential biomarkers for the diagnosis and cancer progression]. / KIM-1 i NGAL jako potencjalne biomarkery w diagnostyce i rozwoju procesu nowotworowego.

On the basis of scientific literature, there is growing evidence that KIM-1 and NGAL are interesting and promising biomarkers not only in acute and chronic inflammatory processes but also in oncogenesis. There are a number of studies which investigate their possible use in diagnosis, treatment and monitoring of therapy effectiveness. The results of recent research suggests that they may play an important role in standard oncology practice. Simultaneous measurement of KIM-1 and NGAL in urine can play a crucial role in carcinogenesis assessment and cancer progression. In the future, they can become rapid diagnostic indicators, which allow one to determine cancer subtype leading to biopsy replacement and therapy improvement. In the present work, beside biochemical characteristics of KIM-1 and NGAL, we will also discuss their role in the diagnosis and assessment of development of cancer.

[Urinalysis in patients at the early stage of acute pancreatitis]. / Badanie ogólne moczu u chorych z ostrym zapaleniem trzustki we wczesnej fazie rozwoju choroby.

Urinalysis is a routine and cheap laboratory test that provides clinically useful information in patients with acute abdominal conditions, including acute pancreatitis. The aim of the study was to assess the relationships between the results of urinalysis and the course of the disease among 65 patients with acute pancreatitis (34 men and 31 women, mean age 61 ± 19 years) at the early phase of the disease, i.e. during the first 72 hours from the onset of symptoms. Mild acute pancreatitis was diagnosed in 47 patients, moderately severe in 13 and severe in 5. The most prevalent abnormalities were proteinuria (43% of patients), high urinary bilirubin (20%), erythrocytes (18%), glucose (18%) and leukocytes (17%). High urinary protein and low specific gravity were associated with more severe acute disease and with acute kidney injury. The severity of bilirubinuria and proteinuria were positively correlated with urine concentrations of neutrophil gelatinase associated lipocalin (NGAL). Urinalysis should be routinely performed in patients with acute pancreatitis.

Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus.

AIMS/HYPOTHESIS: Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-ß-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes. METHODS: Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP. RESULTS: During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM-1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c-statistic for ESRD from 0.828 to 0.832 (p = 0.042). CONCLUSIONS/INTERPRETATION: In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic.

Molecular phenotyping of clinical AKI with novel urinary biomarkers.

Acute kidney injury (AKI) is a common hospital complication. There are no effective treatments to minimize kidney injury or limit associated morbidity and mortality. Currently, serum creatinine and urine output remain the gold standard used clinically in the diagnosis of AKI. Several novel biomarkers can diagnose AKI earlier than elevations of serum creatinine and changes in urine output. Recent long-term observational studies have elucidated a subgroup of patients who have positive biomarkers of AKI but do not meet criteria for AKI by serum creatinine or urine output, termed subclinical AKI. These patients with subclinical AKI have increased risk of both short- and long-term mortality. In this review, we will highlight the implications of what these patients may represent and the need for better phenotyping of AKI by etiology, severity of injury, and ability to recover. We will discuss two AKI biomarkers, neutrophil gelatinase-associated lipocalin (NGAL) and breast regression protein-39 (BRP-39)/YKL-40, that exemplify the need to characterize the complexity of the biological meaning behind the biomarker, beyond elevated levels reporting on tissue injury. Ultimately, careful phenotyping of AKI will lead to identification of therapeutic targets and appropriate patient populations for clinical trials.