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      Urinary Vitamin D-Binding Protein as a Biomarker of Steroid-Resistant Nephrotic Syndrome

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          Abstract

          BACKGROUND

          Idiopathic nephrotic syndrome (NS) is one of the most common glomerular disorders of childhood and is associated with increased urinary vitamin D-binding protein (uVDBP) excretion. We tested the hypothesis that uVDBP represents a biomarker to differentiate steroid-resistant nephrotic syndrome (SRNS) from the more benign forms of steroid-sensitive nephrotic syndrome (SSNS).

          METHODS

          This cross-sectional study included children with SRNS ( n = 24), SSNS ( n = 28), and normal controls ( n = 5). Urine and clinical data were collected from patients. Measurements of uVDBP were performed with a commercially available ELISA kit and normalized to urine creatinine.

          RESULTS

          Concentrations of uVDBP were significantly higher ( P < 0.001) in patients with SRNS (13,659 ng/mL, interquartile range [IQR] 477–22,979) than in patients with SSNS (94 ng/mL, IQR 53–202) and normal controls (23 ng/mL, IQR 22–99, P = 0.002). Significance did not change when the results were corrected for urine creatinine. uVDBP was significantly negatively correlated with estimated glomerular filtration rate (eGFR; R = −0.76, P = 0.03). However, uVDBP was still markedly elevated in patients with SRNS with eGFR >100 mL/minute/1.73 m 2. There was a positive correlation between microalbuminuria (MALB/Cr) and uVDBP ( R = 0.67, P < 0.001). However, uVDBP displayed a much higher discriminatory ability for distinguishing SRNS than MALB/Cr (area under the curve = 0.92 vs 0.67, respectively). An uVDBP cutoff of 362 ng/mL yielded the optimal sensitivity (80%) and specificity (83%) to distinguish SRNS from SSNS.

          CONCLUSIONS

          In this preliminary study, uVDBP represents a noninvasive biomarker that could distinguish SRNS from the more benign SSNS with high discriminatory power.

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          Most cited references25

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          Vitamin D Binding Protein Impact on 25-Hydroxyvitamin D Levels under Different Physiologic and Pathologic Conditions

          There is a high prevalence of vitamin D deficiency worldwide, but how to define vitamin D deficiency is controversial. Currently, the plasma concentration of total 25-hydroxyvitamin D [25(OH)D] is considered an indicator of vitamin D status. The free hormone hypothesis states that protein-bound hormones are inactive while unbound hormones are free to exert biological activity. The majority of circulating 25(OH)D and 1,25(OH)2D is tightly bound to vitamin D binding protein (DBP), 10–15% is bound to albumin, and less than 1% of circulating vitamin D exists in an unbound form. While DBP is relatively stable in most healthy populations, a recent study showed that there are gene polymorphisms associated with race and ethnicity that could alter DBP levels and binding affinity. Furthermore, in some clinical situations, total vitamin D levels are altered and knowing whether DBP is also altered may have treatment implications. The aim of this review is to assess DBP concentration in different physiological and pathophysiological conditions. We suggest that DBP should be considered in the interpretation of 25(OH)D levels.
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            Changing patterns in the histopathology of idiopathic nephrotic syndrome in children.

            It is widely accepted that minimal change nephrotic syndrome (MCNS) is the most common cause of nephrosis in children. Recent studies have demonstrated an increasing incidence of focal segmental glomerulosclerosis (FSGS) in adults. To determine possible changes in the etiology of childhood nephrosis, the clinical charts of 152 pediatric patients diagnosed with idiopathic nephrotic syndrome between 1978 and 1997 were reviewed. Histopathological diagnosis was available in 105 patients. MCNS was present in 35% of all biopsies, whereas FSGS was observed in 31%. Even if we assume that all patients without a histological diagnosis had MCNS (presumptive MCNS), the total incidence of MCNS (biopsy proven + presumptive) in our population was only 55%. We observed a dramatic increase in the incidence of FSGS during recent years. Before 1990, FSGS was diagnosed in 23% of all renal biopsies but increased to 47% afterward (P = 0.02). This pattern was observed in all ethnic groups. In African Americans, there was a trend for an increase in the incidence of FSGS from 38% before 1990 to 69% after 1990. A similar trend was observed in Caucasians (from 20 to 45%) and Hispanics (from 8 to 33%) Hispanics had the highest incidence of MCNS (biopsy proven + presumptive: 73%), followed by Caucasians (53%) and African Americans (37%). The mean age for presentation of nephrotic syndrome in African Americans (8.0 +/- 0.9 years) was higher than in Caucasians (4.1 +/- 0.05) and Hispanics (3.3 +/- 0.5). Our study showed that the incidence of FSGS in children with idiopathic nephrotic syndrome has increased recently. Furthermore, in African American children. FSGS is the most common cause of nephrotic syndrome. These findings may have significant implications in the management of childhood nephrotic syndrome.
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              Differential risk of remission and ESRD in childhood FSGS.

              Focal segmental glomerulosclerosis (FSGS) is the leading cause of steroid-resistant nephrotic syndrome in childhood and the most common form of end stage renal disease (ESRD) from glomerular disease. In order to assess the risk of progression of children with primary FSGS and the impact of proteinuria remission status on disease progression, we undertook this study to describe a cohort of 60 children and adolescents from the Glomerular Disease Collaborative Network. Of the 60 patients included in the cohort, 58% were African American. Median age was 16 years. Proteinuria ranged from 1.0-24.0 g/day/1.73 m(2); 57% were hypertensive, and the median estimated glomerular filtration rate (eGFR) was 90.2 ml/min/1.73 m(2). Complete remission was achieved in 20%, partial remission in 33%, and 47% have not achieved remission during follow-up with all prescribed therapy. Only ACE-I/ARB therapy was predictive of proteinuria remission in multivariate analysis (hazard ratio [HR] 3.35; 95% confidence interval [CI] 1.42-7.92). Renal survival was much improved in patients with complete or partial remission compared with no remission in univariate analysis. In multivariate analysis comparing no remission status, complete remission was associated with a 90% decreased risk of ESRD (HR 0.10, 95% CI 0.01-0.79, p =0.03). In summary, proteinuria remission status is a valid predictor of long-term renal survival in children with FSGS.
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                Author and article information

                Journal
                Biomark Insights
                Biomark Insights
                Biomarker Insights
                Biomarker Insights
                Libertas Academica
                1177-2719
                2016
                13 January 2016
                : 11
                : 1-6
                Affiliations
                [1 ]Assistant Professor, Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
                [2 ]Summer Student, Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
                [3 ]Research Assistant, Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
                [4 ]Clinical Fellow, Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
                [5 ]Professor, Division of Nephrology and Hypertension, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA.
                Author notes
                Article
                bmi-11-2016-001
                10.4137/BMI.S31633
                4712977
                f47ee600-688e-492a-b2a4-71c31e5fbf4a
                © 2016 the author(s), publisher and licensee Libertas Academica Ltd.

                This is an open-access article distributed under the terms of the Creative Commons CC-BY-NC 3.0 License.

                History
                : 13 July 2015
                : 30 September 2015
                : 05 October 2015
                Categories
                Original Research

                Clinical chemistry
                nephrotic syndrome,steroid resistance,vitamin d,focal segmental glomerulosclerosis,minimal change disease,biomarkers

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