Comparative diagnostic utility of different urinary biomarkers during pre-albuminuric stages of non-hypertensive type 2 diabetic nephropathy

Background & objectives: Activation of renin-angiotensin system and tubulointerstitial damage might be seen in pre-albuminuria stage of diabetic nephropathy (DN). Here, diagnostic utility of four urinary biomarkers [Angiotensinogen (Angio), Interleukin (IL)-18, Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Cystatin] during pre-albuminuria stages of non-hypertensive type 2 diabetes patients was studied. Methods: A total of 952 type 2 diabetes mellitus (T2DM) patients were screened for nephropathy [estimated glomerular filtration rate (eGFR) ?120 ml/min and albumin–creatinine ratio (ACR) ?30], and 120 patients were followed up for one year. At one year, they were classified into hyperfiltration (43), normoalbuminuria (29) and microalbuminuria (48) groups. Another 63 T2DM patients without nephropathy were included as controls. Hypertension, patients on angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, eGFR <60 ml/min/1.73 m2 and all proteinuric conditions were excluded. All were subjected to testing for urine protein, ACR, HbA1C, eGFR, along with urinary biomarkers (IL-18, cystatin-C, NGAL and AGT). Comparative analysis of all the diagnostic tests among different subgroups, correlation and logistic regression was done. Results: Urinary IL-18/Cr, cystatin/creatinine (Cr) and AGT/Cr levels were higher in groups of hyperfiltration (13.47, 12.11 and 8.43 mg/g), normoalbuminuria (9.24, 11.74 and 9.15 mg/g) and microalbuminuria (11.59, 14.48 and 10.24 mg/g) than controls (7.38, 8.39 and 1.26 mg/g), but NGAL/Cr was comparable. The area under receiver operating characteristic curve (AUC) and sensitivity of AGT to detect early CKD were higher than ACR and eGFR (0.91 and 90.4%, 0.6 and 40% and 0.6 and 37%, respectively). AUC values of other biomarkers, namely IL-18/Cr, cystatin/Cr and NGAL/Cr, were 0.65, 0.64 and 0.51, respectively. Angio/Cr and IL-18/ Cr showed correlation with log albuminuria (r=0.3, P=0.00, and r=0.28, P=0.00, respectively). NGAL showed correlation with log eGFR (r=0.28 P=0.00). Multivariate logistic analysis showed that odds ratio of developing nephropathy was 7.5 times with higher values of log Angio/Cr. Interpretation & conclusions: Urinary AGT showed a higher diagnostic value than ACR and eGFR followed by IL-18 and cystatin to diagnose DN during pre-albuminuric stages.

NGF and HB-EGF: Potential Biomarkers that Reflect the Effects of Fesoterodine in Patients with Overactive Bladder Syndrome

PURPOSE: To determine whether levels of nerve growth factor (NGF) and heparin-binding epidermal growth factor-like growth factor (HB-EGF) can be used to objectively assess overactive bladder syndrome (OAB) treatment outcome and to evaluate the effects of fixed-dose fesoterodine on OAB symptoms. MATERIALS AND METHODS: This study included 124 participants (62 patients with OAB and 62 controls) in Severance Hospital between 2010 and 2012. In patients with OAB, 4 mg fesoterodine was administered once daily. Repeated evaluations of putative biomarker levels, urine creatinine (Cr) levels, and questionnaire responses, including the Overactive Bladder Symptom Score (OABSS) and the Overactive Bladder Questionnaire (OAB q), were performed from baseline to 16 weeks. RESULTS: Urinary levels of NGF/Cr (OAB: 1.13+/-0.9 pg/mg; control: 0.5+/-0.29 pg/mg) and HB-EGF/Cr (OAB: 8.73+/-6.55 pg/mg; control: 4.45+/-2.93 pg/mg) were significantly higher in subjects with OAB than in controls (p<0.001). After 16 weeks of fixed-dose fesoterodine treatment, urinary NGF/Cr levels (baseline: 1.13+/-0.08 pg/mg; 16 weeks: 0.60+/-0.4 pg/mg; p=0.02) and HB-EGF/Cr levels significantly decreased (baseline: 8.73+/-6.55 pg/mg; 16 weeks: 4.72+/-2.69 pg/mg; p=0.03, respectively). Both the OABSS and OAB q scores improved (p<0.001). However, there were no a statistically significant correlations between these urinary markers and symptomatic scores. CONCLUSION: Urinary levels of NGF and HB-EGF may be potential biomarkers for evaluating outcome of OAB treatment. Fixed-dose fesoterodine improved OAB symptoms. Future studies are needed to further examine the significance of urinary NGF and HB-EGF levels as therapeutic markers for OAB.

Correlation between urinary biomarkers and pathological lesions in drug-induced tubulointerstitial nephritis / 中华内科杂志

Objective To find some urinary biomarkers for differential diagnosis in drug-induced tubulointerstitial nephritis (DTIN) by accessing the relationship between their changes and the pathological processes of DTIN.Methods Forty patients biopsy-proven DTIN and 24 healthy controls were enrolled in this study.The urine samples of DTIN patients were collected on the day of biopsy and were measured for the following biomarkers: urinary TGF-β with enzyme-linked immunosorbent assay (ELISA);urinary IL-6 with radio-immunoassay;N-acetyl-β-D-glucosaminidase (NAG) with enzyme-substrate colorimetric assay;α1-microglobulin (α1-MG) with immune transmission turbidity method.Meanwhile, the pathological changes on renal biopsy were analyzed semi-quantitatively and scored.The relationship between these pathological changes and the urinary biomarkers were analyzed and receiver operating characteristic curve ( ROC curve) of those biomarkers in distinguishing different pathological lesions were constructed.Results Urinary α1- MG levels were positively correlated to interstitial edema, inflammatory cell infiltration and tubular atrophy, while urinary IL-6 were negatively correlated to the above parameters.Urinary NAG had positive relationship with inflammatory cell infiltration and tubular atrophy, while urinary TGF-β had positive relationship with tubular atrophy.ROC analysis results indicated that the area under curve (AUC) of α1-MG was larger than that of NAG (0.797 vs 0.734, P ＜ 0.05 ).Combined measurement of α1-MG and NAG could enhance the sensitivity of detecting interstitial inflammatory cell infiltration.For detecting interstitial edema and tubular atrophy, only α1-MG had statistical significance ( AUC = 0.723, P = 0.027;AUC = 0.774, P = 0.008,respectively).Conclusions Urinary α1-MG and NAG levels can reflect the severity of interstitial inflammatory infiltration, combined measurement of both can enhance sensitivity.Urinary α1-MG level can also reflect the degree of interstitial edema and tubular atrophy.