Urine Biomarkers Predict the Cause of Glomerular Disease

Abstract

Diagnosis of the type of glomerular disease that causes the nephrotic syndrome is necessary for appropriate treatment and typically requires a renal biopsy. The goal of this study was to identify candidate protein biomarkers to diagnose glomerular diseases. Proteomic methods and informatic analysis were used to identify patterns of urine proteins that are characteristic of the diseases. Urine proteins were separated by two-dimensional electrophoresis in 32 patients with FSGS, lupus nephritis, membranous nephropathy, or diabetic nephropathy. Protein abundances from 16 patients were used to train an artificial neural network to create a prediction algorithm. The remaining 16 patients were used as an external validation set to test the accuracy of the prediction algorithm. In the validation set, the model predicted the presence of the diseases with sensitivities between 75 and 86% and specificities from 92 to 67%. The probability of obtaining these results in the novel set by chance is 5 ؋ 10 ؊8 . Twenty-one gel spots were most important for the differentiation of the diseases. The spots were cut from the gel, and 20 were identified by mass spectrometry as charge forms of 11 plasma proteins: Orosomucoid, transferrin, ␣-1 microglobulin, zinc ␣-2 glycoprotein, ␣-1 antitrypsin, complement factor B, haptoglobin, transthyretin, plasma retinol binding protein, albumin, and hemopexin. These data show that diseases that cause nephrotic syndrome change glomerular protein permeability in characteristic patterns. The fingerprint of urine protein charge forms identifies the glomerular disease. The identified proteins are candidate biomarkers that can be tested in assays that are more amenable to clinical testing.

Iron-Related Proteins

“…We were unable to identify a single candidate protein that could distinguish between these diseases. However, we found the 11 candidate protein biomarkers that have been used by Varghese et al to predict the diagnosis of FSGS, lupus nephritis, membranous nephropathy, and diabetic nephropathy in adult HIV-negative patients, using an artificial neural network analysis (11). Thus, it remains to be determined whether a similar analysis could be used to identify HIVinfected children that might have HIVAN.…”

“…This knowledge will facilitate the identification of children at high risk of developing these diseases; the administration of disease-oriented fluid, hematologic, pharmacologic, and nutritional therapies; as well as the planning of early referrals to intensive care units with expertise in pediatric renal replacement therapies and plasmapheresis. Therefore, we carried out this study to identify new candidate protein urine biomarkers in HIV-infected children, and to determine whether several protein urine biomarkers used in HIV-negative adults to predict the diagnosis of other glomerular diseases were found in the urine of HIV-infected children (11).…”

Zinc α2-Glycoprotein: A Multidisciplinary Protein

“…These proteins can be used as markers for specific and accurate clinical analyses of diabetic nephropathy. The peptide fingerprint of urine protein glomerular disease was analyzed, and they found that ZAG is a biomarker for glomerular disease (40). In conclusion, ZAG not only is a biomarker for prostate and breast cancer but also covers the most commonly occurring cancer.…”

“…Although the exact mechanism by which ZAG actively participates in tumor proliferation is not known, a large body of data exists in favor of the expression of ZAG with respect to the stages of tumor (39)(40)(41)(42). ZAG is designated as a potential biomarker of different types of carcinomas (6,7,27,35,38,(43)(44)(45)(46).…”

Optimizing a Proteomics Platform for Urine Biomarker Discovery

“…In addition, urine transferrin levels are elevated in patients with diabetic nephropathy (20 -22), and higher urine transferrin levels predict the onset of microalbuminuria in diabetic patients (20 -22). In three independent proteomics scans, ␣ 1 -antitrypsin, a serine protease inhibitor, was present at higher levels in urine and renal tissue of patients with diabetic nephropathy compared with controls (22)(23)(24). Higher levels of ␣ 1B -glycoprotein have also been reported previously in urine of patients with proteinuric diabetic nephropathy compared with normoalbuminuric diabetics (25).…”