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1.  Tubular damage in chronic systolic heart failure is associated with reduced survival independent of glomerular filtration rate 
Heart (British Cardiac Society)  2010;96(16):1297-1302.
The prognostic impact of reduced glomerular filtration rate (GFR) in chronic heart failure (CHF) is increasingly recognised, but little is known about tubular damage in these patients.
To investigate the prevalence of tubular damage, and its association with GFR, and prognosis in patients with CHF.
Methods and results
In 90 patients with CHF, GFR and effective renal plasma flow (ERPF) were measured ([125I] iothalamate and [131I]hippuran clearances). The tubular markers neutrophil gelatinase-associated lipocalin (NGAL), N-acetyl-β-D-glucosaminidase (NAG) and kidney injury molecule 1 (KIM-1) as well as urinary albumin excretion were determined in 24 h urine collections. Mean GFR was 78±26 ml/min/1.73 m2. Urinary NGAL (175 (70—346) mg/g creatinine (gCr)), NAG (12 (6—17) U/gCr) and KIM-1 (277 (188—537) ng/gCr) levels were increased compared with 20 healthy controls (all p<0.001). Urinary NAG, but not NGAL or KIM-1 correlated with GFR (r=−0.34, p=0.001) and ERPF (r=−0.29, p=0.006). Both NAG (r=0.21, p=0.048) and KIM-1 (r=0.23, p=0.033) correlated with plasma N-terminal pro-brain natriuretic peptide levels. Both urinary KIM-1 (HR=1.15 (95% CI 1.02 to 1.30) per 100 ng/gCr increase, p=0.025) and NAG (HR=1.42 (95% CI 1.02 to 1.94) per 5 U/gCr increase, p=0.039), were associated with an increased risk of death or heart failure hospitalisations, independent of GFR.
Tubular damage, as indicated by increased urinary concentrations of NGAL, NAG and KIM-1 is common in patients with CHF and mildly reduced GFR. Both urinary KIM-1 and NAG showed prognostic information additional to GFR. These findings suggest an important role for tubular damage and tubular markers in cardiorenal interaction in heart failure.
PMCID: PMC3480323  PMID: 20659949
2.  Urinary Biomarkers for The Prediction of Reversibility in Acute-on-Chronic Renal Failure 
Disease markers  2013;34(3):179-185.
BACKGROUND: There is no reliable clinical test to predict the reversibility of acute-on-chronic renal failure. We study whether urinary biomarkers could be used as a noninvasive prognostic marker in patients with acute-on-chronic renal failure.
METHODS: We studied 39 adult patients with pre-existing chronic renal impairment presenting to us with acute-on-chronic renal failure. Urinary neutrophil gelatinase-associated lipocalin (NGAL) level was measured. The mRNA of kidney injury molecule-1 (KIM-1), interleukin-18 (IL-18), alpha-1-microglobulin (α1M), sodium/hydrogen exchanger-3 (NHE3), beta-2 microglobulin (β2M), and N-acetyl-β-D-glucosaminidase (NAG) in urinary sediment were quantified.
RESULTS: Urinary NGAL level significantly correlated with the serum creatinine at presentation (r = 0.762, p < 0.0001) but not baseline serum creatinine. Urinary sediment β2M expression significantly correlated with baseline glomerular filtration rate (GFR) (r = –0.400, p = 0.012). Urinary α1M and NHE3 expressions were significantly higher in ischemic acute tubular necrosis than other causes of acute kidney injury (p < 0.0001 and p = 0.006, respectively). Urinary α1M expression significantly correlated with the degree of improvement in renal function (r = 0.387, p = 0.026), as well as the estimated GFR 6 months later (r = 0.386, p = 0.027).
CONCLUSION: In patients with acute-on-chronic renal failure, urinary NGAL level correlates with the severity of renal failure, while urinary α1M expression correlates with the degree of renal function recovery. Quantification of urinary α1M mRNA may be developed as an non-invasive tool for risk stratification of this group of patients.
PMCID: PMC3809980  PMID: 23324582
Acute kidney injury; biomarker; proteinuria
3.  Clinical Characteristics and Disease Predictors of a Large Chinese Cohort of Patients with Autosomal Dominant Polycystic Kidney Disease 
PLoS ONE  2014;9(3):e92232.
Autosomal dominant polycystic kidney disease (ADPKD) is a relentlessly progressing form of chronic kidney disease for which there is no cure. The aim of this study was to characterize Chinese patients with ADPKD and to identify the factors which predict cyst growth and renal functional deterioration.
To analyze disease predicting factors we performed a prospective longitudinal observational study in a cohort of 541 Chinese patients with ADPKD and an eGFR ≥30 ml/min/1.73 m2. Patients were followed clinically and radiologically with sequential abdominal magnetic resonance imaging (MRI). Clinical characteristics and laboratory data were related to changes in estimated glomerular filtration rate (eGFR) and total kidney volume (TKV). A linear regression model was developed to analyze the factors which determine eGFR and TKV changes.
The age range of this unselected cohort ranged from 4 to 77 years. Median follow-up time was 14.3±10.6 months. Although inter-individual differences in eGFR and TKV were large, there was a consistent link between these two parameters. Baseline log10-transformed TKV and urinary protein/creatinine ratio were identified as the major predictors for a faster eGFR decline and were associated with a higher TKV growth rate. Interestingly, a lower thrombocyte count correlated significantly with lower eGFR (r = 0.222) and higher TKV (r = 0.134).
This large cohort of Chinese patients with ADPKD provides unique epidemiological data for comparison with other cohorts of different ethnicity. In Chinese patients we identified a lower thrombocyte count as a significant predictor of disease progression. These results are important for the design of future clinical trials to retard polycystic kidney disease progression.
PMCID: PMC3961326  PMID: 24651850
4.  Evidence of Uncoupling between Renal Dysfunction and Injury in Cardiorenal Syndrome: Insights from the BIONICS Study 
PLoS ONE  2014;9(11):e112313.
The objective of the study was to assess urinary biomarkers of renal injury for their individual or collective ability to predict Worsening renal function (WRF) in patients with acutely decompensated heart failure (ADHF).
In a prospective, blinded international study, 87 emergency department (ED) patients with ADHF were evaluated with biomarkers of cardiac stretch (B type natriuretic peptide [BNP] and its amino terminal equivalent [NT-proBNP], ST2), biomarkers of renal function (creatinine, estimated glomerular filtration rate [eGFR]) and biomarkers of renal injury (plasma neutrophil gelatinase associated lipocalin [pNGAL], urine kidney injury molecule-1 [KIM-1], urine N-acetyl-beta-D-glucosaminidase [NAG], urine Cystatin C, urine fibrinogen). The primary endpoint was WRF.
26% developed WRF; baseline characteristics of subjects who developed WRF were generally comparable to those who did not. Biomarkers of renal function and urine biomarkers of renal injury were not correlated, while urine biomarkers of renal injury correlated between each other. Biomarker concentrations were similar between patients with and without WRF except for baseline BNP. Although plasma NGAL was associated with the combined endpoint, none of the biomarker showed predictive accuracy for WRF.
In ED patients with ADHF, urine biomarkers of renal injury did not predict WRF. Our data suggest that a weak association exists between renal dysfunction and renal injury in this setting ( NCT#0150153).
PMCID: PMC4227686  PMID: 25386851
5.  Urinary Expression of Novel Tissue Markers of Kidney Injury After Ureteroscopy, Shockwave Lithotripsy, and in Normal Healthy Controls 
Journal of Endourology  2013;27(12):1455-1462.
Background and Purpose: Shockwave lithotripsy (SWL) and ureteroscopy (URS) are minimally invasive treatment alternatives for kidney stones. Although less invasive, SWL subjects the renal parenchyma to a high level of energy and the potential to cause renal injury. The ability to detect renal injury post-SWL in a reliable and noninvasive way would be clinically beneficial. Kidney injury molecule 1 (KIM-1) and N-acetyl-β-D-glucosaminidase (NAG) are two proteins secreted by the kidney into the urine and have been found to be sensitive markers of acute kidney injury in transplant patients. The aim of this work was to measure urinary levels of KIM-1 and NAG in patients with kidney stone who were treated by SWL or URS and in nonstone volunteers.
Patients and Methods: Patients with kidney stones who were treated by SWL (n=50) or URS (n=10) were recruited. Voided urine samples were collected before and 2 to 3 hours after URS and SWL. In addition, further urinary specimens were collected 2 days and 2 weeks post-SWL treatment. Voided urine samples from healthy volunteers were also collected.
Results: Mean KIM-1 values were increased in patients with kidney stones when compared with volunteers. KIM-1 and NAG levels significantly increased post-SWL and returned to baseline within 2 weeks post-SWL. Poor kidney function was significantly associated with increased biomarker activity both in baseline and post-SWL measurements. There was no significant change in urinary KIM-1 and NAG concentrations before and after URS.
Conclusions: Kim-1 and NAG levels significantly increased post-SWL treatment suggesting a potential role for these urinary markers in identifying patients at higher risk of tissue injury.
PMCID: PMC3997088  PMID: 24180435
6.  Kidney volume and function in autosomal dominant polycystic kidney disease 
The significance of total kidney volume (TKV) as a biomarker of kidney function in autosomal dominant polycystic kidney disease (ADPKD) is controversial and has been reappraised.
Between 2007 and 2012, 64 patients were followed with a mean 39.7-month observation period. TKV measurements by magnetic resonance imaging and estimation of renal function with estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease equation and 24-h urine creatinine clearance were repeated annually.
TKV and its adjusted parameters (height-adjusted, body surface area-adjusted and log-converted TKV [log-TKV]) correlated with eGFR significantly. Among them, the correlation coefficient of log-TKV was most significant (r = −0.6688, p < 0.001). The eGFR slope correlated negatively with TKV slope (p < 0.05). TKV increased faster and became larger as chronic kidney disease (CKD) stage advanced. As age advanced, eGFR declined significantly (p < 0.001), but the eGFR slope remained constant. There was no significant correlation between TKV and age, but the log-TKV slope became smaller as age advanced. If baseline TKV was large, the eGFR slope was steeper (p < 0.05), which suggests that eGFR declines faster in patients with larger kidney volume.
TKV is confirmed as a clinically meaningful surrogate marker in ADPKD. Log-TKV correlates with eGFR most significantly. Higher rates of kidney enlargement and larger kidney volume are associated with a more rapid decrease in kidney function. Kidney function decreased faster as CKD stage advanced, but its declining slope did not change significantly by age, at least after ~30 years of age.
PMCID: PMC3923113  PMID: 23864346
Autosomal dominant polycystic kidney disease; Glomerular filtration rate; Kidney volume
7.  Biomarkers for early detection of sickle nephropathy 
American journal of hematology  2011;86(7):559-566.
Renal complications affect nearly 30–50% of adults with sickle cell anemia (SCA), causing significant morbidity and mortality. Standard renal function tests like serum creatinine and glomerular filtration rate become abnormal in this disease only when renal damage has become extensive and largely irreversible. Moreover, not all patients develop sickle nephropathy (SN). Therefore, noninvasive biomarkers that predict early onset of SN are necessary. We performed a cross-sectional analysis for nephropathy in 116 patients with sickle cell disease, analyzing urinary kidney injury molecule-1 (KIM-1), liver-type fatty acid binding protein (L-FABP), N-acetyl-b-D-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL) and transforming growth factor-β1 (TGF-β), together with conventional renal biomarkers (urine albumin and osmolality, and serum creatinine and cystatin C estimated GFR) during routine clinic visits when patients were at steady-state/baseline. We observed a distinct biomarker pattern: KIM-1 and NAG emerged as biomarkers with a strong association with albuminuria. Surprisingly, and in contrast to other acute/chronic renal disorders, NGAL, L-FABP, and TGF-β levels did not show any relationship with albuminuria in patients with SCA. Our study identifies potential biomarkers for SN, and suggests longitudinal validation of these biomarkers for early detection of SN, so that therapeutic interventions can be applied before renal damage becomes irreversible.
PMCID: PMC4167419  PMID: 21630304
8.  Urinary N-Acetyl-beta-D-glucosaminidase as an Early Marker for Acute Kidney Injury in Full-Term Newborns with Neonatal Hyperbilirubinemia 
Disease Markers  2014;2014:315843.
Purpose. To investigate renal function estimated by markers in full-term newborns with hyperbilirubinemia. Methods. A total of 332 full-term newborns with hyperbilirubinemia and 60 healthy full-term newborns were enrolled. Total serum bilirubin, serum creatinine (Cr), serum blood urea nitrogen (BUN), serum cystatin C (Cys-C), urinary beta-2-microglobulin (β2MG) index, and urinary N-acetyl-beta-D-glucosaminidase (NAG) index were measured before and after treatment. All newborns were divided into three groups according to total serum bilirubin levels: group 1 (221-256), group 2 (256-342), and group 3 (>342). Results. The control group and group 1 did not differ significantly in regard to serum Cr, serum BUN, serum Cys-C, urinary β2MG index, and urinary NAG index. Urinary NAG index in group 2 was significantly higher than that in control group (P < 0.001). Between control group and group 3, serum Cys-C, urinary β2MG index, and urinary NAG index differed significantly. The significant positive correlation between total serum bilirubin and urinary NAG index was found in newborns when total serum bilirubin level was more than 272 μmol/L. Conclusions. High unconjugated bilirubin could result in acute kidney injury in full-term newborns. Urinary NAG might be the suitable marker for predicting acute kidney injury in full-term newborns with hyperbilirubinemia.
PMCID: PMC4094716  PMID: 25049438
9.  Urinary N-acetyl-beta-D-glucosaminidase activity in workers exposed to inorganic lead. 
Urinary N-acetyl-beta-D-glucosaminidase (NAG) had been shown to be a useful early marker of renal injury. In workers exposed to lead it seems to be the only early marker but the dose response and dose effect relations are weak. Furthermore, the significance and underlying mechanism of increased urinary NAG activity is far from clear. By studying the isoenzyme profiles of urinary NAG, the significance and underlying mechanism may be further clarified. The heat labile (NAG-A) and heat stable (NAG-B) isoenzyme profiles of 128 workers exposed to lead from a lead stabiliser factory were analysed. NAG activity was expressed as total NAG, NAG-A, and NAG-B activity as well as ratios (NAG-B/total NAG and NAG-B/NAG-A). Exposure indices included the recent concentration of blood lead (BPb), a cumulative blood lead index (TBPb), and the recent change in concentration of blood lead (CBPb). The NAG indices correlated best with CBPb. Nearly 50% of the variation in NAG-B activity could be explained by the combination of all three exposure indices but only the CBPb was highly significant. When these exposure indices were entered separately into the regression equation, CBPb accounted for 36.3% of the variation in NAG-B activity, 5.7% was accounted for by TBPb and 2.7% by BPb. There was also no dose-effect or dose-response relation between the NAG variables and BPb or TBPb groups. With CBPb, there were dose-effect and dose-response relations. With CBPb, there was an increase in NAG variables in the group with more than 25% increase in blood lead over the past six months. The increase in NAG activity in this study is likely to be due to a recent increase in concentration of blood lead and hence presumably a recent rise in renal burden of inorganic lead. This suggests that the increase in urinary NAG activity is a form of acute response to a sharp increase in renal burden of lead, rather than to a cumulative dose. Heat stable NAG is part of the lysosomal membrane and is present in the urine when there is breakdown of lysosomes. Our data therefore contradict suggestions that the increase in urinary NAG activity is due to exocytosis.
PMCID: PMC1127917  PMID: 8111460
10.  Urinary Proteomic Biomarkers for Diagnosis and Risk Stratification of Autosomal Dominant Polycystic Kidney Disease: A Multicentric Study 
PLoS ONE  2013;8(1):e53016.
Treatment options for autosomal dominant polycystic kidney disease (ADPKD) will likely become available in the near future, hence reliable diagnostic and prognostic biomarkers for the disease are strongly needed. Here, we aimed to define urinary proteomic patterns in ADPKD patients, which aid diagnosis and risk stratification. By capillary electrophoresis online coupled to mass spectrometry (CE-MS), we compared the urinary peptidome of 41 ADPKD patients to 189 healthy controls and identified 657 peptides with significantly altered excretion, of which 209 could be sequenced using tandem mass spectrometry. A support-vector-machine based diagnostic biomarker model based on the 142 most consistent peptide markers achieved a diagnostic sensitivity of 84.5% and specificity of 94.2% in an independent validation cohort, consisting of 251 ADPKD patients from five different centers and 86 healthy controls. The proteomic alterations in ADPKD included, but were not limited to markers previously associated with acute kidney injury (AKI). The diagnostic biomarker model was highly specific for ADPKD when tested in a cohort consisting of 481 patients with a variety of renal and extrarenal diseases, including AKI. Similar to ultrasound, sensitivity and specificity of the diagnostic score depended on patient age and genotype. We were furthermore able to identify biomarkers for disease severity and progression. A proteomic severity score was developed to predict height adjusted total kidney volume (htTKV) based on proteomic analysis of 134 ADPKD patients and showed a correlation of r = 0.415 (p<0.0001) with htTKV in an independent validation cohort consisting of 158 ADPKD patients. In conclusion, the performance of peptidomic biomarker scores is superior to any other biochemical markers of ADPKD and the proteomic biomarker patterns are a promising tool for prognostic evaluation of ADPKD.
PMCID: PMC3542378  PMID: 23326375
11.  Correlation between glomerular filtration rate and urinary N acetyl-beta-D glucosaminidase in children with persistent proteinuria in chronic glomerular disease 
Korean Journal of Pediatrics  2012;55(4):136-142.
Urinary excretion of N acetyl-beta-D glucosaminidase (NAG) and β2-microglobulin (β2-M) was increased in the presence of proximal tubular damage. Based on these urinary materials, we investigated the ability of expecting renal function in chronic glomerular diseases. In this study, we evaluated the relationship between glomerular filtration rate (GFR) urinary NAG, and urinary β2-M.
We evaluated 52 children with chronic kidney disease at the Chung-Ang University Hospital between January 2003 and August 2009. We investigated the 24-hour urinalysis and hematologic values in all 52 patients. Serum creatinine, creatinine clearance (Ccr), serum cystatin C, urinary β2-M and urinary NAG were measured.
Out of 52 patients, there were 13 children with minimal change in disease, 3 children with focal segmental glomerulosclerosis, 17 children with immunoglobulin A nephropathy, 15 children with Henoch-Schönlein purpua nephritis, 3 children with poststreptococcal glomerulonephritis, and 1 child with thin glomerular basement membrane disease. In these patients, there were significant correlation between the Ccr and urinary NAG (r=-0.817; P<0.01), and between the GFR (as determined by Schwartz method) and urinary NAG (r=-0.821; P<0.01). In addition, there was a significant correlation between the GFR (as determined by Bokencamp method) and urinary NAG (r=-0.858; P<0.01).
In our study, there was a significant correlation between the GFR and urinary NAG, but there was no correlation between the GFR and urinary β2-M, suggesting that the GFR can be predicted by urinary NAG in patients with chronic glomerular disease.
PMCID: PMC3346836  PMID: 22574074
Proteinuria; Glomerular filtration rate; N acetyl-beta-D glucosaminidase
12.  Evaluation of urinary tissue inhibitor of metalloproteinase-2 in acute kidney injury: a prospective observational study 
Critical Care  2014;18(6):716.
Tissue inhibitor of metalloproteinase-2 (TIMP-2) is an emerging acute kidney injury (AKI) biomarker. We evaluated the performance of urinary TIMP-2 in an adult mixed ICU by comparison with other biomarkers that reflect several different pathways of AKI.
In this study, we prospectively enrolled 98 adult critically ill patients who had been admitted to the adult mixed ICU. Urinary TIMP-2 and N-acetyl-β-d-glucosaminidase (NAG) and plasma neutrophil gelatinase-associated lipocalin (NGAL), interleukin-6 (IL-6) and erythropoietin (EPO) were measured on ICU admission. We evaluated these biomarkers’ capability of detecting AKI and its severity as determined by using the Kidney Disease Improving Global Outcomes serum creatinine criteria, as well as its capacity to predict in-hospital mortality. The impact of sepsis, the leading cause of AKI in ICUs, was also evaluated.
We found AKI in 42 patients (42.9%). All biomarkers were significantly higher in AKI than in non-AKI. In total, 27 patients (27.6%) developed severe AKI. Urinary TIMP-2 was able to distinguish severe AKI from non-severe AKI with an area under the receiver operating characteristic curve (AUC-ROC) of 0.80 (95% confidence interval, 0.66 to 0.90). A total of 41 cases (41.8%) were complicated with sepsis. Although plasma NGAL and IL-6 were increased by sepsis, urinary TIMP-2 and NAG were increased not by sepsis, but by the presence of severe AKI. Plasma EPO was increased only by septic AKI. In-hospital mortality was 15.3% in this cohort. Urinary TIMP-2 and NAG, and plasma NGAL, were significantly higher in non-survivors than in survivors, although plasma IL-6 and EPO were not. Among the biomarkers, only urinary TIMP-2 was able to predict in-hospital mortality significantly better than serum creatinine.
Urinary TIMP-2 can detect severe AKI with performance equivalent to plasma NGAL and urinary NAG, with an AUC-ROC value higher than 0.80. Furthermore, urinary TIMP-2 was associated with mortality. Sepsis appeared to have only a limited impact on urinary TIMP-2, in contrast to plasma NGAL.
Electronic supplementary material
The online version of this article (doi:10.1186/s13054-014-0716-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4300076  PMID: 25524453
13.  Sensitivity and Specificity of a Single Emergency Department Measurement of Urinary Neutrophil Gelatinase–Associated Lipocalin for Diagnosing Acute Kidney Injury 
Annals of internal medicine  2008;148(11):810-819.
A single serum creatinine measurement cannot distinguish acute kidney injury from chronic kidney disease or prerenal azotemia.
To test the sensitivity and specificity of a single measurement of urinary neutrophil gelatinase–associated lipocalin (NGAL) and other urinary proteins to detect acute kidney injury in a spectrum of patients.
Prospective cohort study.
Emergency department of Columbia University Medical Center, New York, New York.
635 patients admitted to the hospital with acute kidney injury, prerenal azotemia, chronic kidney disease, or normal kidney function.
Diagnosis of acute kidney injury was based on the RIFLE (risk, injury, failure, loss, and end-stage) criteria and assigned by researchers who were blinded to experimental measurements. Urinary NGAL was measured by immunoblot, N-acetyl-β-D-glucosaminidase (NAG) by enzyme measurement, α1-microglobulin and α1-acid glycoprotein by immunonephelometry, and serum creatinine by Jaffe kinetic reaction. Experimental measurements were not available to treating physicians.
Patients with acute kidney injury had a significantly elevated mean urinary NGAL level compared with the other kidney function groups (416 μg/g creatinine [SD, 387]; P = 0.001). At a cutoff value of 130 μg/g creatinine, sensitivity and specificity of NGAL for detecting acute injury were 0.900 (95% CI, 0.73 to 0.98) and 0.995 (CI, 0.990 to 1.00), respectively, and positive and negative likelihood ratios were 181.5 (CI, 58.33 to 564.71) and 0.10 (CI, 0.03 to 0.29); these values were superior to those for NAG, α1-microglobulin, α1-acid glycoprotein, fractional excretion of sodium, and serum creatinine. In multiple logistic regression, urinary NGAL level was highly predictive of clinical outcomes, including nephrology consultation, dialysis, and admission to the intensive care unit (odds ratio, 24.71 [CI, 7.69 to 79.42]).
All patients came from a single center. Few kidney biopsies were performed.
A single measurement of urinary NGAL helps to distinguish acute injury from normal function, prerenal azotemia, and chronic kidney disease and predicts poor inpatient outcomes.
PMCID: PMC2909852  PMID: 18519927
14.  Rationale and design of the RESOLVE trial: lanreotide as a volume reducing treatment for polycystic livers in patients with autosomal dominant polycystic kidney disease 
BMC Nephrology  2012;13:17.
A large proportion of patients with autosomal dominant polycystic kidney disease (ADPKD) suffers from polycystic liver disease. Symptoms arise when liver volume increases. The somatostatin analogue lanreotide has proven to reduce liver volume in patients with polycystic liver disease. However, this study also included patients with isolated polycystic liver disease (PCLD). The RESOLVE trial aims to assess the efficacy of lanreotide treatment in ADPKD patients with symptomatic polycystic livers. In this study we present the design of the RESOLVE trial.
This open-label clinical trial evaluates the effect of 6 months of lanreotide in ADPKD patients with symptomatic polycystic livers. Primary outcome is change in liver volume determined by computerised tomography-volumetry. Secondary outcomes are changes in total kidney volume, kidney intermediate volume and renal function. Furthermore, urinary (NGAL, α1-microglobulin, KIM-1, H-FABP, MCP-1) and serum (fibroblast growth factor 23) biomarkers associated with ADPKD disease severity are assessed to investigate whether these biomarkers predict treatment responses to lanreotide. Moreover, safety and tolerability of the drug in ADPKD patients will be assessed.
We anticipate that lanreotide is an effective therapeutic option for ADPKD patients with symptomatic polycystic livers and that this trial aids in the identification of patient related factors that predict treatment response.
Trial registration number
Clinical NCT01354405
PMCID: PMC3368739  PMID: 22475206
ADPKD; Urinary biomarkers; Polycystic liver disease; Lanreotide
15.  Indices of renal tubular function in perinatal asphyxia 
Aims—To determine and compare two urinary indices of renal tubular function, N-acetyl-glucosaminidase (NAG) and β2-microglobulin (β2M), in healthy term neonates and babies with perinatal asphyxia.
METHODS—In a prospective case-control study using asphyxiated (n=35) and normal control (n=55) infants, urinary NAG and β2M were assayed at 24-48 hours of life, 4-6 days, and 4-6 weeks.
RESULTS—NAG and β2M were significantly increased at 24-48 hours and 4-6 days in the asphyxiated infants compared with the controls. Increased NAG values reflect the degree of perinatal asphyxia more than do β2M. Gentamicin also increased NAG excretion, but to a lesser extent than did perinatal asphyxia.
CONCLUSIONS—NAG (+/- β2M) may be a useful marker of perinatal asphyxia. Urinary NAG concentrations correlate with the severity of perinatal asphyxia.

 Keywords: perinatal asphyxia; renal tubular function; N-acetyl-glucosaminidase
PMCID: PMC1720666  PMID: 9279185
16.  Renal tubular function of workers exposed to low levels of cadmium. 
Cadmium induced renal tubular effects were examined in 65 female workers in a factory manufacturing nickel cadmium batteries. Urinary beta 2-microglobulin (beta 2m), urinary N-acetyl-D-glucosaminidase activity (NAG), and serum creatinine and serum urea concentrations were used to assess the renal effects. Of the four measures, only urinary NAG and urinary beta 2m showed a strong positive correlation with blood cadmium concentrations (r = 0.49 and 0.43 respectively); NAG showed a weaker correlation with urinary cadmium concentrations (r = 0.35). Urinary beta 2m has weak correlation with urinary cadmium (r = 0.04). Only urinary NAG showed a significant deterioration in renal function among the exposed group. NAG detects the largest proportion of abnormalities among the exposed group. Abnormal urinary beta 2m is detected in only 15.4% of the workers, half of whom have blood cadmium above 10 micrograms/l. The proportion of abnormalities detected by urinary NAG differs significantly from the proportion of abnormalities detected by urinary beta 2m (p less than 0.01). The age adjusted mean urinary NAG excretion showed a significant rise with urinary cadmium of above 3 micrograms/g creatinine. Urinary beta 2m failed to show any significant rise. With blood cadmium concentrations, the age adjusted mean urinary NAG excretion showed a rise from 1 microgram/l of blood cadmium followed by a plateau between blood cadmium concentrations of 3-10 micrograms/l. No significant rise in mean urinary excretion in beta 2m was seen until blood cadmium concentrations exceeded 10 micrograms/l.
PMCID: PMC1009747  PMID: 2649143
17.  Diagnostic value of N-acetyl-β-D-glucosaminidase for the early prediction of acute kidney injury after percutaneous nephrolithotripsy 
The present observational study was undertaken in order to evaluate the diagnostic value of urinary N-acetyl-β-D-glucosaminidase (NAG) for the prediction of acute kidney injury (AKI) in patients after percutaneous nephrolithotripsy (PNL). Pre- and post-operative patient data were collected for 90 patients who underwent PNL between September 2008 and December 2010. The patients included 64 males and 26 females with an average age of 52.8±9.7 years. Pre- and post-operative urinary NAG was measured by colorimetric assay and serum creatinine levels were determined for comparative analysis. Urinary NAG levels significantly increased after PNL compared to pre-operative levels (P<0.05). AKI occurred in 11 cases after surgery. A comparison of the AKI and non-AKI groups revealed no significant differences in age, gender ratio or baseline creatinine levels (P>0.05); however, there were significant differences between the groups as regards surgical duration, post-operative infection rate, C-reactive protein levels and number of hospital days (P<0.05). NAG levels were significantly higher in the AKI compared to the non-AKI group after surgery (P<0.05). The diagnostic utility of the increase in urinary NAG 24 h after surgery was assessed by receiver operating characteristic (ROC) analysis. For an increase in NAG of 235.44%, the area under the ROC curve was 0.878 (P<0.01) and the sensitivity and specificity for AKI diagnosis were 81.8 and 91.1%, respectively. Urinary NAG significantly increased in patients suffering from AKI after surgery. This parameter is more sensitive than serum creatinine and can reflect the impairment of kidney function at an earlier stage. The surgical duration and post-operative infection rate are possible risk factors for AKI. Urinary NAG may have some clinical value in the early diagnosis of AKI after surgery.
PMCID: PMC3524284  PMID: 23251267
acute kidney injury; N-acetyl-β-D-glucosaminidase; percutaneous nephrolithotripsy
18.  Evaluation of urine biomarkers of kidney injury in Polycystic Kidney Disease 
Kidney International  2012;81(8):784-790.
Progressive disruption of renal tubular integrity in the setting of increased cellular proliferation and apoptosis is a feature of ADPKD. Here we evaluated the effect of these processes on the expression of NGAL and IL-18, markers of tubular injury, in rodent models and in the cyst fluid and urine of patients with ADPKD. Two mouse models where Pkd2 was inactivated which resulted in early or adult onset cysts, were used to evaluate NGAL levels. Further, the Han:SPRD rat model of polycystic disease was used to study IL-18 levels. In four annual serial urine samples from 107 patients with ADPKD in the Consortium for Radiologic Imaging for the Study of Polycystic Kidney Disease (CRISP) study, NGAL and IL-18 excretion rates were determined in conjunction with measures of total kidney volume and estimated GFR (eGFR) by the MDRD equation. Kidneys from affected mice and rats showed prominent expression of NGAL and IL-18/IL-18R, respectively, in epithelial cells lining kidney cysts. In human ADPKD cyst fluid, both NGAL and IL-18 were elevated. In CRISP patients, the mean percentage increase in total kidney volume was 5.4 /year and the mean decline in eGFR 2.4 mL/min/year. The trend of increased mean urine NGAL and IL-18 over three years was statistically significant; however, there was no association of tertiles of IL-18 or quartiles of NGAL and the change in total kidney volume or eGFR over this period. Thus, urinary NGAL and IL-18 excretion are mildly and stably elevated in ADPKD, but do not correlate with changes in total kidney volume or kidney function. This may be due, in part, to the lack of communication between individual cysts and the urinary collecting system in this disorder.
PMCID: PMC3319327  PMID: 22258321
surrogate; NGAL; IL-18; biomarker
19.  Glomerular and Tubular Damage Markers Are Elevated in Patients With Diabetes 
Diabetes Care  2011;34(4):975-981.
We investigated in a cross-sectional study the levels of serum and urinary damage markers in diabetic patients (n = 94) and nondiabetic control subjects (n = 45) to study the association of glomerular (IgG), proximal tubular (kidney injury molecule [KIM]-1, N-acetyl-β-d-glucosaminidase [NAG], neutrophil gelatinase–associated lipocalin [NGAL], and cystatin C), and distal tubular (heart fatty acid–binding protein [H-FABP]) damage markers with kidney disease severity, as assessed by albuminuria and estimated glomerular filtration rate (eGFR).
Damage markers were measured in triplicate in fresh morning urine samples and in plasma.
Of the diabetic patients, 41 were normoalbuminuric, 41 were microalbuminuric, and 12 were macroalbuminuric. Urinary NAG (ninefold), NGAL (1.5-fold), and H-FABP (3.5-fold) were significantly elevated in normoalbuminuric diabetic patients compared with nondiabetic control subjects. Urinary concentrations of all markers increased per albuminuria stratum, except KIM-1. All urinary damage markers, except KIM-1, were significantly associated with albuminuria, independent of age, sex, and plasma concentrations of the corresponding biomarker (standard βs between 0.35 and 0.87; all P ≤ 0.001). All urinary damage markers, except KIM-1, were significantly associated with the eGFR in univariate models (standard βs between −0.38 and −0.21; all P < 0.04). After adjusting for age, sex, plasma concentration of the corresponding damage marker, and albuminuria, only the association of H-FABP with eGFR remained significant (standard β −0.26; P = 0.037).
Glomerular and tubular markers are associated with albuminuria, independently of eGFR, suggesting that albuminuria reflects both glomerular and tubulointerstitial damage. Only urinary H-FABP is associated with eGFR independently of albuminuria and, therefore, may be a promising urinary damage marker to assess diabetic kidney disease.
PMCID: PMC3064060  PMID: 21307379
20.  Serum uric acid, kidney volume and progression in autosomal-dominant polycystic kidney disease 
Hyperuricemia has been implicated in the development and progression of chronic kidney disease, both in animal experiments and in clinical studies. As a potentially modifiable risk factor, we examined whether serum uric acid levels correlate with early hypertension, kidney volume and progression to end-stage renal disease (ESRD) in autosomal-dominant polycystic kidney disease (ADPKD).
Retrospective analysis of a prospective observational study of the natural history of ADPKD, conducted at the University of Colorado between 1985 and 2005. Included are 680 ADPKD adults who provided data on blood pressure, renal volume, renal function, uric acid, age at the onset of ESRD or last known age without ESRD. Serum uric acid levels were examined as a continuous variable and as gender-specific quartiles. The main outcome of interest was age at the onset of ESRD; secondary outcomes were hypertension onset before age 30 years and total kidney volume (TKV) at the study visit.
Subjects with early-onset hypertension had higher age-adjusted serum uric acid levels than those with no or late-onset hypertension despite similar creatinine clearance. After adjusting for age, gender and creatinine clearance, there was a 5.8% increase in TKV and 4.1% increase in TKV/body surface area for every 1 mg/dL increase in uric acid (P = 0.007). The multivariate-adjusted Cox regression demonstrated a greater hazard ratio for ESRD for subjects in the 4th and 3rd quartiles of uric acid compared with the 1st [4.8 (2.6–8.9; P < 0.001) and 2.9 (1.6–5.3; P < 0.001)].
Higher serum uric acid levels are associated with earlier onset of hypertension, larger kidney volume and increased hazard for ESRD in ADPKD independent of gender, body mass index and renal function at the study visit. Randomized interventional studies will be necessary to examine whether treating hyperuricemia has a protective role in ADPKD.
PMCID: PMC3616764  PMID: 23222419
autosomal-dominant polycystic kidney disease; end-stage renal disease; hypertension; kidney volume; uric acid
21.  Comparison of Kidney Injury Molecule-1 and Other Nephrotoxicity Biomarkers in Urine and Kidney Following Acute Exposure to Gentamicin, Mercury, and Chromium 
Sensitive biomarkers are needed to detect kidney injury at the earliest stages. The objective of this study was to determine whether the appearance of kidney injury molecule-1 (Kim-1) protein ectodomain in urine and kidney injury molecule-1/hepatitis A viral cellular receptor-1 (Kim-1/Havcr1) gene expression in kidney tissue may be more predictive of renal injury after exposure to nephrotoxicants when compared to traditionally used biomarkers. Male Sprague-Dawley rats were injected with a range of doses of gentamicin, mercury (Hg; HgCl2), or chromium (Cr; K2Cr2O7). The results showed that increases in urinary Kim-1 and kidney Kim-1/Havcr1 gene expression paralleled the degree of severity of renal histopathology and were detected at lower doses of nephrotoxicants when compared to blood urea nitrogen (BUN), serum creatinine, and urinary N-acetyl-β-D-glucosaminidase (NAG). In a time course study, urinary Kim-1 was elevated within 24 h after exposure to gentamicin (100 mg/kg), Hg (0.25 mg/kg), or Cr (5 mg/kg) and remained elevated through 72 h. NAG responses were nephrotoxicant dependent with elevations occurring early (gentamicin), late (Cr), or no change (Hg). At 72 h, after treatment with any of the three nephrotoxicants, there was increased Kim-1 immunoreactivity and necrosis involving ∼50% of the proximal tubules; however, only urinary Kim-1 was significantly increased, while BUN, serum creatinine, and NAG were not different from controls. In rats treated with the hepatotoxicant galactosamine (1.1 mg/kg), serum alanine aminotransferase was increased, but no increase in urinary Kim-1 was observed. Urinary Kim-1 and kidney Kim-1/Havcr1 expression appear to be sensitive and tissue-specific biomarkers that will improve detection of early acute kidney injury following exposure to nephrotoxic chemicals and drugs.
PMCID: PMC2744478  PMID: 17934191
acute kidney injury; nephrotoxicity biomarkers; kidney injury molecule-1; mercury; chromium; gentamicin
22.  Comparative Analysis of Urinary Biomarkers for Early Detection of Acute Kidney Injury Following Cardiopulmonary Bypass 
The purpose of this study was to compare the performance of six candidate urinary biomarkers, kidney injury molecule 1 (KIM-1), N-acetyl-β-(D)-glucosaminidase (NAG), neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), cystatin C, and α-1 microglobulin, measured 2 hours following cardiopulmonary bypass (CPB) for the early detection of acute kidney injury (AKI) in a prospective cohort of patients undergoing cardiac surgery. 103 subjects were enrolled, AKI developed in 13%. Urinary KIM-1 achieved the highest area under-the-receiver-operator-characteristic curve (AUC = 0.78, 95% CI 0.64-0.91), followed by IL-18 and NAG. Only urinary KIM-1 remained independently associated with AKI after adjustment for a preoperative AKI prediction score (Cleveland Clinic Foundation score; P= 0.02), or CPB perfusion time (P = 0.006). In this small pilot-cohort, KIM-1 performed best as an early biomarker for AKI. Larger studies are needed to further explore the role of biomarkers for early detection of AKI following cardiac surgery.
PMCID: PMC2743298  PMID: 19572801
Acute kidney injury; early detection; urinary biomarker; cardiac surgery
23.  Serum Cystatin C and Tubular Urinary Enzymes as Biomarkers of Renal Dysfunction in Type 2 Diabetes Mellitus 
Renal tubulointerstitium plays an important role in the development and progression of diabetic nephropathy. The aim of this study was to assess serum cystatin C and 2 renal tubular enzymes, neutrophil gelatinase associated lipocalin (NGAL) and N-acetyl-beta-D-glucosaminidase (NAG), as screening markers for early renal dysfunction in patients with type 2 diabetes mellitus (T2DM). ROC curve analysis showed that urinary NAG is the most sensitive marker of microalbuminuria and early renal damage with sensitivity of 83.3%, while serum cystatin C was the most sensitive and specific marker of macroalbuminuria and damage progress with sensitivity of 70.8% and specificity of 83.3% versus 70.6% and 83.3% for uNGAL; and 64.7% and 66.7% for NAG, respectively. Our data indicate that urinary NAG is the most sensitive marker for early renal damage in diabetic patients. However, for damage progress, serum cystatin C is the most sensitive and specific marker for follow-up and monitoring renal dysfunction.
PMCID: PMC3738377  PMID: 23966807
diabetic nephropathy; neutrophil gelatinase-associated lipocalin; N-acetyl-beta-D-glucosaminidase; cystatin C
24.  The Effects of n-3 Long-Chain Polyunsaturated Fatty Acid Supplementation on Biomarkers of Kidney Injury in Adults With Diabetes 
Diabetes Care  2013;36(6):1462-1469.
Long-chain n-3 polyunsaturated fatty acid (n-3 PUFA) supplements may have renoprotective effects in patients with diabetes, but previous trials have been inconsistent. We performed a randomized controlled trial of n-3 PUFA supplementation on urine albumin excretion and markers of kidney injury in adults with type 2 diabetes.
We conducted a randomized, placebo-controlled, two-period crossover trial to test the effects of 4 g/day of n-3 PUFA supplementation on markers of glomerular filtration and kidney injury in adults with adult-onset diabetes and greater than or equal to trace amounts of proteinuria. Each period lasted 6 weeks and was separated by a 2-week washout. The main outcome was urine albumin excretion and, secondarily, markers of kidney injury (kidney injury molecule-1, N-acetyl β-d-glucosaminidase [NAG], neutrophil gelatinase-associated lipocalin [NGAL], and liver fatty acid–binding protein [LFABP]), serum markers of kidney function (cystatin C, β2-microglobulin, and creatinine), and estimated glomerular filtration rate (eGFR).
Of the 31 participants, 29 finished both periods. A total of 55% were male, and 61% were African American; mean age was 67 years. At baseline, mean BMI was 31.6 kg/m2, median eGFR was 76.9 mL/min/1.73 m2, and median 24-h urine albumin excretion was 161 mg/day. Compared with placebo, n-3 PUFA had nonsignificant effects on urine albumin excretion (−7.2%; 95% CI −20.6 to 8.5; P = 0.35) and significant effects on urine NGAL excretion (−16% [−29.1 to −0.5%]; P = 0.04). There was no effect on serum markers of kidney function or eGFR. In subgroup analyses, there were significant decreases in 24-h urinary excretion of albumin, NGAL, LFABP, and NAG among participants taking medications that block the renin-angiotensin-aldosterone system (RAAS).
These results suggest a potential effect of n-3 PUFA supplementation on markers of kidney injury in patients with diabetes and early evidence of kidney disease. In the context of prior studies, these results provide a strong rationale for long-term trials of n-3 PUFA on chronic kidney disease progression.
PMCID: PMC3661851  PMID: 23275364
25.  Novel Assays for Detection of Urinary KIM-1 in Mouse Models of Kidney Injury 
Toxicological Sciences  2012;131(1):13-25.
Editor’s Highlight: Sensitive and early noninvasive biomarkers of renal toxicity are needed to augment or replace current biomarkers. This report describes the development and validation of two bioassays for mouse urinary KIM-1 that may be of clinical value. Using a microbead-based assay and a quantitative dipstick assay, these assays demonstrated sensitivity and stability for detection of KIM-1 in models of renal toxicity when other biomarkers remained unchanged.
Kidney injury molecule-1 (KIM-1) has been qualified by the Food and Drug Administration and European Medicines Agency as a urinary biomarker to monitor preclinical nephrotoxicity in rats and on a case-by-case basis for the translation of potentially nephrotoxic drugs into first-in human studies. Although mouse models are widely employed in preclinical studies, few urinary biomarker studies have been performed in mice due to limited urine availability and lack of sensitive assays. Here, we report the development and validation of two different assays for quantitative assessment of mouse urinary KIM-1 (uKIM-1) and compare the sensitivity of KIM-1 relative to other standard markers in ischemia reperfusion and aristolochic acid (AA)–induced kidney injury in mice. A sensitive, reproducible, and quantitative microbead-based KIM-1 ELISA was established, which requires only 10 μl urine for triplicate determination with an assay range of 12.21 pg/ml to 50ng/ml. The second assay is a laminar flow dipstick assay, which has an assay range of 195 pg/ml to 50ng/ml and provides quantitative assessment of KIM-1 in 15min. uKIM-1 levels increased with increasing time of ischemia or time after AA administration. After only 10-min ischemia followed by 24-h reperfusion, uKIM-1 was significantly elevated by 13-fold, whereas serum creatinine (sCr), blood urea nitrogen, N-acetyl-β-glucosaminidase (NAG), and proteinuria levels did not change. After AA administration, uKIM-1 levels were significantly upregulated by greater than threefold within 12h, whereas sCr and NAG levels were unchanged. Mouse KIM-1 was stable for multiple freeze-thaw cycles, for up to 5 days at room temperature and up to at least an year when stored at −80°C.
PMCID: PMC3621351  PMID: 23019274
kidney injury molecule-1; mouse KIM-1 assay; ischemia/reperfusion injury; aristolochic acid; nephrotoxicity biomarkers; acute kidney injury.

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