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Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression.

ABSTRACT: Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy. We further compared DNase I levels in human native and transplanted kidneys to determine if the disease depended on autologous renal genes, or whether the nephritic process proceeded also in transplanted kidneys. The data indicate that reduced renal DNase I expression level relates to serious progression of lupus nephritis in murine, human native, and transplanted kidneys. Notably, silencing of renal DNase I correlated with loss of DNase I endonuclease activity in the urine samples. Thus, urinary DNase I levels may therefore be used as a marker of lupus nephritis disease progression and reduce the need for renal biopsies.

SUBMITTER: Pedersen HL

PROVIDER: S-EPMC6065113 | biostudies-literature | 2018 Jul

REPOSITORIES: biostudies-literature

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Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression.

Pedersen Hege L HL Horvei Kjersti D KD Thiyagarajan Dhivya D Norby Gudrun E GE Seredkina Natalya N Moroni Gabriella G Eilertsen Gro Ø GØ Holdaas Hallvard H Strøm Erik H EH Bakland Gunnstein G Meroni Pier-Luigi PL Rekvig Ole P OP

The journal of pathology. Clinical research 20180406 3

Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, imm ...[more]

PMID: 29624903

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Project description:ObjectiveThere is an urgent need to identify novel biomarkers of LN to reflect renal histological changes. This study aims to investigate urinary G3BP levels in LN patients and their association with renal disease activity both clinically and pathologically.MethodsThis is a cross-sectional study. A total of 119 lupus nephritis patients were recruited. Thirty patients with chronic kidney diseases (CKD) and 27 healthy volunteers were also recruited as controls. Urinary G3BP was tested by ELISA. Renal histopathology was reviewed by an experienced renal pathologist. Other clinical variables were collected through chart review.ResultsThe levels of uG3BP were significantly increased in active LN patients compared to those in inactive LN (p<0.001), CKD patients (p=0.01), and healthy controls (p<0.001). ROC analysis indicated a good discrimination ability of uG3BP to differentiate active LN from CKD patients (AUC=0.7), inactive LN (AUC=0.76), or healthy controls (AUC=0.87). uG3BP was positively correlated with SLEDAI (ρ=0.352, p<0.001), rSLEDAI (ρ=0.302, p<0.001), and SLICC RAS (ρ=0.465, p<0.001), indicating a role as a biomarker of disease activity. It also correlated with clinical parameters, including 24-h urine protein, ESR, and serum C3 levels. In patients with 24-h urine protein > 3.0 g/24h, uG3BP levels were higher in proliferative LN than in membranous LN (p=0.04). They could discriminate the two pathogenic types of LN (AUC=0.72), and they also positively correlated with AI (ρ=0.389, p=0.008) and scores of hyaline deposits (ρ=0.418, p=0.006). While in patients with 24-h urine protein ≤ 3.0 g/24h, uG3BP levels were not significantly different between proliferative and membranous LN, and there was no apparent relationship between uG3BP levels with AI or with scores of hyaline deposits, but they correlated positively with scores of cellular/fibrocellular crescents (ρ=0.328, p=0.04).ConclusionuG3BP is a non-invasive biomarker for clinically and histologically reflecting disease activity. It is associated with active histological changes and can be used as a surrogate biomarker when the renal biopsy is impractical.

Dataset Information

Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression.

Publications

Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression.

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