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Uromodulin, also known as Tamm–Horsfall protein, is the most abundant protein in urine. It has recently been reported that uromodulin exists in a small amount in blood and that its concentration correlates with the estimated glomerular filtration rate (eGFR). First, we generated anti-human uromodulin mouse monoclonal antibodies (mAb(s)) and established a specific enzyme-linked immunosorbent assay (ELISA) for uromodulin. We then performed an observational clinical study to determine if there was a correlation between serum uromodulin concentration and estimates of kidney function and whether the serum uromodulin value could be a biomarker in clinical nephrology. The clinical study included 308 patients with and without chronic kidney disease and healthy volunteers. Serum concentrations of creatinine, cystatin C, and uromodulin were measured and correlations were sought between the eGFR calculated from the creatinine and cystatin C levels and the serum uromodulin concentration. There was a good correlation between the serum uromodulin concentration and the eGFR value calculated from the creatinine (r = 0.76) and cystatin C (r = 0.79) levels. The mean serum uromodulin level in the group with an eGFR > 90 mL/min/1.73 m2 calculated using cystatin C was significantly higher than that in the group with an eGFR of 80–89 mL/min/1.73 m2. The serum uromodulin measurement could be a useful biomarker for identification of patients with early deterioration of kidney function.

Background Uromodulin, also known as Tamm-Horsfall protein, is the most abundant protein in urine. It has recently been reported that uromodulin exists in a small amount in blood and that its concentration correlates with the estimated glomerular filtration rate (eGFR). However, its clinical significance has not been clarified and there are no relevant data for the Japanese population. Method First, we generated anti-human uromodulin mouse monoclonal antibodies and established a specific enzyme-linked immunosorbent assay for uromodulin. We then performed an observational clinical study to determine if there was a correlation between serum uromodulin concentration and estimates of kidney function and whether the serum uromodulin value could be a biomarker in clinical nephrology. The clinical study included 308 patients with and without chronic kidney disease and healthy volunteers. Serum concentrations of creatinine, cystatin C, and uromodulin were measured and correlations were sought between the eGFR calculated from the creatinine and cystatin C levels and the serum uromodulin concentration. Results There was a good correlation between the serum uromodulin concentration and the eGFR value calculated from the creatinine (r=0.76) and cystatin C (r=0.79) levels. The mean serum uromodulin level in the group with an eGFR >90 mL/min/1.73 m 2 calculated using cystatin C was significantly higher than that in the group with an eGFR of 80–89 mL/min/1.73 m 2 . Conclusions The serum uromodulin measurement could be a useful biomarker for identification of patients with early deterioration of kidney function.

The validity of the Birmingham Vasculitis Activity Score (BVAS) as an index of disease activity and a predictor of the prognosis and outcome in patients with MPA has not yet been established in Japan. We conducted a retrospective study of the data of 73 patients with MPA who were followed up for at least 2 years. We divided the patients into two groups according to the BVAS, namely, the high-BVAS group (≥16) and the low-BVAS group (

An observational cohort study was conducted to compare the performance of the RIFLE (risk, injury, failure, loss and end-stage kidney disease), AKIN (acute kidney injury network) and conventional graded criteria to identify acute kidney injury (AKI) following SCT and to predict long-term mortality in 141 myeloablative allogeneic SCT (m-allo), 60 non-myeloablative allogeneic SCT (nm-allo) and 48 autologous SCT (auto) cases. The AKIN criteria had less ability to identify patients as having the lowest category, stage 1 (analogous to RIFLE risk): 33% (37%) in m-allo, 23% (32%) in nm-allo and 8.3% (16.7%) in auto. Cox regression showed that categories higher than the intermediate stage were independent predictors of mortality in all three definitions. The areas under receiver operating characteristic curves showed that both definition systems had similar and significant ability to predict mortality (0.643-0.649 in m-allo and 0.734-0.766 in nm-allo, respectively). These abilities of the conventional graded criteria were comparable with those of the RIFLE criteria. The RIFLE criteria have greater sensitivity than the AKIN criteria to identify patients with AKI and therefore are more favorable as a uniform definition system for post-SCT AKI. However, the RIFLE criteria do not improve on the clinical relevance of the conventional graded criteria.

Background Chronic kidney disease (CKD) seems to be common in long-term survivors of haematopoietic cell transplantation (HCT). However, the range of its frequency is very wide, likely due to variability in the definitions of CKD and the periods of follow-up. Methods We conducted a cross-sectional and retrospective study in 158 adults who received myeloablative allogeneic HCT for lymphohaematologic malignancies at least 3 years ago and are alive today. The mean survival time was 6.15 +/- 4.88 years (range: 3-16 years). CKD was defined as a sustained decrease in glomerular filtration rate (GFR) or persistent proteinuria for a period more than 3 months. GFR was calculated based on serum creatinine (Cr) using the Modification of Diet in Renal Disease formula. Serum Cr and proteinuria were measured at least on three occasions separated by one or more months before the investigation. CKD was classified according to the National Kidney Foundation CKD staging. Proteinuria was defined as positive dipstick test > or =1+. The factors associated with the presence of CKD with a decrease of GFR (CKD > or = stage 3) were examined using multivariate logistic regression analysis, adjusted for demographic and clinical characteristics. Results The prevalence of proteinuria was found in 36 out of 158 patients (22.8%). The prevalence of each CKD stage was as follows: Stage 0 (no CKD), 98 patients (62.0%); Stage 1, 18 patients (11.4%); Stage 2, 15 patients (9.5%); Stage 3, 8 patients (5.1%); Stage 4, 10 patients (6.3%) and Stage 5, 9 patients (5.7%). Initiation of chronic dialysis treatment or transplant was performed in seven CKD stage-5 patients (4.4%) at a mean of 10.9 +/- 3.72 years after HCT. Multivariate analysis identified acute kidney injury with HCT [odds ratio (OR), 9.920; 95% confidence interval (CI), 2.084-39.68; P = 0.0051], hypertension after HCT (OR, 4.031; 95% CI, 1.044-13.06; P = 0.0346) and survival time after HCT (OR, 4.275; 95% CI, 2.823-23.04; P = 0.0481) as significant factors associated with the presence of CKD > or = stage 3. Conclusions A remarkably high percentage of long-term survivors had evidence of proteinuria and all stages of CKD. CKD in transplant recipients may result from incomplete recovery from acute renal insults, hypertension and increasing longevity. The CKD cohort should be at a great risk for end-stage renal disease and cardiovascular morbidity and mortality. The burden of CKD should be recognized as a significant public health problem.

Background/Aims: S100A12 induces vascular inflammation contributing to the development of atherosclerosis. Serum S100A12 concentration is shown to be elevated in patients with chronic kidney disease (CKD), however the reason remains unclear. Methods: Transcriptional levels of S100A12 and RAGE (receptor for advanced glycation end products) were measured in peripheral leukocytes by quantitative real-time RT-PCR. Subjects were 40 patients with CKD stage 4-5, 20 of whom were affected with cardiovascular disease (CVD), and 20 healthy subjects. Serum concentrations of S100A12 and soluble RAGE were measured using enzyme-linked immunosorbent assay. Results: The serum concentration of S100A12 was significantly higher in CKD patients than in healthy subjects (78.5 ± 70.5 vs. 23.7 ± 19.2 ng/ml, p = 0.0035), but that of soluble RAGE was not. The relative quantity of S100A12 mRNA was significantly greater in leukocytes from CKD patients than in those from healthy subjects [mean (95% confidence interval of the mean): 3.1 (2.2-3.9) vs. 1.2 (0.8-1.7), p = 0.0001], however that of RAGE mRNA was not. The serum concentration of S100A12 was significantly correlated with the relative quantity of S100A12 mRNA among uremic CKD patients (r2 = 0.656, p < 0.0001). Both the serum concentration and gene expression of S100A12 were significantly higher in patients who had CVD than in those who did not. Conclusion: Excessive expression of the S100A12 gene in uremic leukocytes is relevant to its increased serum concentration, particularly in those affected with CVD.

Introduction: Stem cell transplantation (SCT) involves a great risk of acute kidney injury (AKI), which is largely committed to fatality derived from SCT. Liver-type fatty acid-binding protein (L-FABP) is a 15kDa protein expressed in human renal proximal tubular cells, and is shed into urine in response to renal tissue ischemia or oxidative stress. Urinary L-FABP (uL-FABP) has been reported to be not only a sensitive biomarker to detect incipient AKI but also a potential marker for something more than a measure of renal insult. This study addressed utility of uL-FABP, as it has not been fully understood on the clinical platform of SCT. Patients and Methods: A prospective cohort study was conducted in 81 patients who received allogeneic SCT in our hospital from April 2009 to March 2012 (median age, 49 years; median [range] follow-up period, 771 [2-1923] days). All had hematological malignancies, and were recipients of the first SCT. Associations of increased uL-FABP before executing conditioning therapy (at baseline) and clinical outcomes including incidence of AKI, non-relapse mortality (NRM), and overall survival (OS) were investigated. AKI was defined, based on the creatinine (Cr) criteria of the 2013 Kidney Disease Global Outcomes. AKI that developed within the first 30 days after SCT was considered in this study. The recipients were stratified into an elevated and a normal uL-FABP group at baseline, according to the reference value for healthy adult individuals (8.5µg/gCr). Hazard ratio (HR) with its 95% confidence interval (CI) of uL-FABP elevation was calculated for OS using the Cox proportional hazard model and for NRM using the Fine-Gray proportional hazards model, adjusted for confounders which had P -values ≤ 0.2 in univariate analyses. Results: Patients had been diagnosed with acute myeloid leukemia (n = 36), acute lymphoid leukemia (n = 23), myelodysplastic syndrome (n = 17), and myeloproliferative neoplasm (n = 5). The elevated and normal uL-FABP groups included 17 (21%) and 64 (79%) patients, respectively. The proportion of high disease risk was significantly greater in the elevated than in the normal uL-FAB P group (70.6 % vs. 31.3%, P = 0.005). There were no significant differences in age, serum Cr level, and the proportion of gender, hematopoietic cell transplantation comorbidity index (HCT-CI) ≥3, myeloablative conditioning regimen, stem-cell sources (bone marrow, peripheral blood, cord blood), related donor type and matched human leukocyte antigen compatibility. AKI emerged in 28 recipients (34.6%) at day 30? following SCT (median [range], 14 [0-30] days). The cumulative incidence [95% CI] of AKI was significantly greater in the elevated than in the normal uL-FABP group (64.7% [36-83.1 %] vs. 26.6% [16.4-37.8 %], P Conclusions: uL-FABP is a simple and non-invasive measurement to target patients at increased risk of AKI, NRM and OS following allogeneic SCT. The presence of antecedent subclinical renal injury, which can be detected by uL-FABP elevation at baseline, may provide prognostic information beyond renal outcome after allogeneic SCT. Disclosures No relevant conflicts of interest to declare.

Abstract 1998 Background: Microalbuminuria is a risk factor for the development of chronic kidney disease (CKD), cardiovascular disease and mortality in the general population. We studied if the incidence of microalbuminuria following hematopoietic stem cell transplantation (SCT) could be a warning sign of the future CKD and all-cause mortality. Method: A 1-year prospective cohort study was conducted in 29 patients (46.3±12.5 years) receiving allogeneic myeloablative SCT. Patients with prevalent CKD and those who died by 1 month after SCT were excluded from the cohort. Albumin to creatinine ratio (ACR) in a morning urine sample was consecutively measured before conditioning therapy (baseline), at the time of SCT, days 7 and 14, and 1 month after SCT. Microalbuminuria was defined as ACR ≥30mg/girl. CKD was defined as a decrease in estimated glomerular filtration rate (eGFR) less than 60 ml/min/1.73m2, sustained at least for 3 months. Cumulative incidence of CKD or mortality or both was assessed by the Kaplan-Meier method. Multivariate Cox regression analysis was used to calculate the hazard ratio (HR) of developing these outcomes within 1 year, adjusted for covariates with clinical and statistical significance. Results: The prevalence of microalbuminuria was 6.9% at baseline, and increased to 62.1% at the day of SCT. It varied among the time points; 62.1% on day 7, 48.3% on day 14 and 51.7% on 1 month, respectively. Mortality within 1 year was 27.6%. Cumulative incidence of CKD or mortality or both was significantly higher in the group with □emicroalbuminuria on 1 month' than in the opposite. [figure1] In addition, the presence of □emicroalbuminuria on 1 month' was significantly associated with each outcome: for CKD, HR 14.5, 95% confidence interval (CI) 2.88 to 121, P=0.0006; for death, HR 11.7, 95% CI 1.58 to 252, P=0.0138; for either CKD or death, HR 16.6, 95% CI 3.79 to 151, P=0.0001, respectively. Conclusion: The incidence of microalbuminuria following SCT is a promising predictor of the development of CKD and short-term mortality. Disclosures: No relevant conflicts of interest to declare.

Stem cell transplantation (SCT) involves a great risk of acute kidney injury (AKI). Urinary liver-type fatty acid-binding protein (uL-FABP) is a sensitive biomarker to detect kidney damage before an increase in serum creatinine (Cr); however, the utility of uL-FABP is not fully understood in the platform of SCT. A prospective study was conducted in 84 allogeneic SCT recipients to ascertain a link between the uL-FABP level before preparative procedures and AKI incidence after SCT. The association between them was analyzed using Gray's method and a multivariate Fine-Gray proportional hazards regression model. The recipients were stratified into high and low uL-FABP groups, according to the reference value for healthy subjects (8.4 μg/g Cr). AKI developed more frequently in the high (n = 20) than low (n = 64) group (55.0% versus 26.6% at day 30, P = .005), and high uL-FABP was an independent risk for the emergence of AKI (hazard ratio, 2.78; 95% confidence interval, 1.24 to 6.22, P = .01). In conclusion, increased baseline uL-FABP, which may indicate previous incipient kidney injury, is linked with a high risk of AKI after allogeneic SCT.